Compounds which have a protective activity with respect to the action of toxins and of viruses with an intracellular mode of action

ABSTRACT

The subject matter of the present invention is novel families of compounds which are aromatic amine, imine, aminoadamantane and benzodiazepine derivatives, medicaments comprising same and the use thereof as inhibitors of the toxic effects of toxins with intracellular activity, such as, for example, ricin, and of viruses that use the internalization pathway for infecting cells.

The subject of the present invention is novel families of compounds which are aromatic amine, imine, aminoadamantane and benzodiazepine derivatives, medicaments comprising same and the use thereof as inhibitors of the toxic effects of toxins with intracellular activity, such as, for example, ricin, and of viruses that use the internalization pathway for infecting cells.

Toxins with an intracellular mode of action, or AB toxins, are enzymes that are organized into several domains: a catalytic domain A which carries the toxic activity and one or more B domains which provide cell recognition and enable transmembrane translocation of the A fragment into the cytoplasm (Falnes, P. O.; Sandvig, K. Curr. Opin. Cell. Biol. 2000, 12, 407). There are many bacterial toxins with intracellular activity: for example, and nonexhaustively, diphtheria toxin and cholera toxin have an A domain which carries an ADP-ribosyltransferase enzyme activity; the major clostridial toxins have a glucosyltransferase activity; botulinum toxin, tetanus toxin and anthrax lethal toxin are metalloproteases; Shiga toxins and ricin have an N-glucosidase activity.

More particularly, ricin is a toxalbumin produced by a shrub of the family Euphorbiaceae, the castor oil plant (Ricinus communis). It is present at a concentration ranging from 1% to 10% in the castor oil plant seed.

It is more specifically a 66 kDa glycoprotein composed of two chains linked by a disulfide bridge. The A chain (RTA, 267 amino acids) performs the catalytic function of ricin (N-glucosidase), while the B chain (RTB, lectin of 262 residues) plays the role of transporter allowing ricin to enter the cell.

The ribosomal-RNA depurination enzymatic activity, located on the A chain, causes the arrest of protein synthesis in poisoned cells and results in cell death.

The B chain has two galactose-binding sites and enables binding of the toxin to glycoreceptors present at the cell surface. The ricin can then penetrate into these cells via multiple endocytosis pathways, so as to reach the trans-Golgi network, where it is conveyed to the endoplasmic reticulum (ER) by retrograde transport.

The toxin is then partially unfolded and the A chain is translocated into the cytosol by the Sec61p translocon which is normally used to translocate newly formed proteins into the ER or to transport incorrectly folded proteins out of the ER and to the cytoplasm so as to be degraded therein. Ricin is capable of escaping this proteolysis, thereby allowing it to bind to the ribosome with great efficiency and to cleave the adenine at position 4324 (hereinafter A4324) of the 28S RNA of the 60S ribosomal subunit. It can thus inactive up to 2000 ribosomes per minute.

Ricin is a cytotoxin which can be easily extracted in large amounts. Its toxicity differs according to the routes of introduction: via the digestive route, because it is absorbed little or inactivated by the digestive enzymes, it is approximately 1000 times less toxic than via the pulmonary route (inhalation) or the parenteral route. There are many symptoms of poisoning, which depend on the route of introduction, and they appear in a few hours and can result in death in 2 to 3 days. There is no antidote in the event of poisoning, treatment being essentially symptomatic. Since ricin is also very soluble in water and can disperse in aerosol form, this toxin is considered to be a major bioterrorist agent (category B agent on the list of the US centers for disease control (CDC, Atlanta)).

In view of the potential for the use of ricin, of other intracellular toxins or of viruses as a biological weapon, it is therefore essential to have medical countermeasures which inhibit the action of a toxin or of a virus.

In order to counter the threat posed by ricin, several types of antitoxins have been developed: neutralizing antibodies, enzymatic activity inhibitors (small molecules and substrate analogs, soluble receptor mimics).

The enzymatic activity inhibitors were described following the elucidation of the mechanism of action of ricin studied firstly by Robertus et al. (Lord, J. M.; Robertus, L. M.; Robertus, J. D. FASEB J. 1994, 8, 201). This author described the depurination mechanism of ricin, the N-glycosylase attacking the 28S RNA of the ribosome. After cleavage of an adenine base (A4324), the rRNA obtained will no longer be able to bind the elongation factors necessary for the movement of the ribosome along the mRNA, which stops protein synthesis and causes death of the cell.

The adenosine targeted is stabilized at the active site by formation of H bonds between the purine ring of the adenosine and certain residues of RTA: valine at position 81 (V81), glutamic acid at position 177 (E177) and arginine at position 180 (R180).

R180 will subsequently allow partial protonation of the adenine base, weakening the link between the base and the ribose. The adenine is then released and the oxonium ion formed, stabilized by E177, is trapped by the water activated by R180, thus forming the ribose.

Thus, there are among the enzyme activity inhibitors:

-   -   the small molecules: these are molecules which will, for         example, bind to ricin at its catalytic site and prevent         ribosome depurination. Molecular modeling studies have allowed         the group of Robertus to discover the first inhibitor of the         enzymatic activity of ricin: pteroic acid and also a derivative         represented below.

However, pteroic acid, and also its derivative, are mediocre inhibitors of the N-glycosylase activity, with an inhibition constant of about 0.6 mM (Miller, D.; Ravikumar, K.; Shen, H.; Suh, J.; Kerwin, S.; Robertus, J. D. J. Med. Chem. 2002, 45, 90. Yan, X. et al. J. Mol. Biol. 1997, 266, 1043).

Since ricin recognizes a very precise sequence in the 28S RNA, the SRL loop (Sarcin-Ricin Loop), inhibitors were designed on the basis of this nucleotide sequence. They are transition state analogs of the natural substrate for ricin which have noncleavable groups at the level of the target adenine. The studies by Schramm (Schramm, V. L. et al. Biochemistry 2001, 40 (23), 6845; Roday, S. et al. Biochemistry 2004, 43, 4923) thus made it possible to identify various inhibitors, one of the best compounds of which (P14) is represented below. This modified RNA is capable of inhibiting the enzymatic activity in vitro, with a K_(i) of 0.18 μM.

In addition, the development of circular oligonucleotides derived from the sequence of the SRL loop is materialized through the obtaining of molecules which inhibit RTA at micromolar and nanomolar concentrations (Sturm, M. B.; Roday S.; Schramm, V. L. J. Am. Chem. Soc., 2007, 129, 5544-5550).

In vitro selection methods were also used to generate RNA ligands, or aptamers, specific for the RTA catalytic chain. These aptamers bear no resemblance to the natural RTA substrate (SRL loop) and are not depurinated by ricin. This study made it possible to identify an aptamer of 31 nucleotides (31RA) capable of interacting with RTA (high-affinity complex, Kd=7.3 nM) and of competitively inhibiting ribosome depurination (IC₅₀=100 nM) (Hesselberth, J. R.; Miller, D.; Robertus, J. D.; Ellington, A. D. J. Biol. Chem. 2000, 275, 4937).

The therapeutic potential of all these enzymatic inhibitors nevertheless appears to be weak. This is because they are compounds that are active only on enzymatic tests; no cell protection or protection on animals has been reported for these molecules. Furthermore, these molecules exhibit deficiencies such as a weak efficacy as regards pteroic acid and its derivatives, or instability in biological media and poor effectiveness in penetrating cells, as regards the RNA derivatives.

Neutralizing monoclonal antibodies have also been developed. Thus, antibodies directed against the RTB chain are capable of protecting mice poisoned with 10 LD50 (Lemley, P. V.; Amanatides, P.; Wright, D. C. Hybridoma 1994, 13, 417. Guo, J. W.; Shen, B. F.; Feng, J. N.; Sun, Y. X.; Yu, M.; Hu, M. R. Hybridoma 2005, 24, 263. Furukawa-Stoffer, T. L.; Mah, D. C.; Cherwonogrodzky, J. W.; Weselake, R. J. Hybridoma 1999, 18, 505).

Several studies are in the process of being carried out in order to develop neutralizing “humanized” antibodies that can be used in the event of ricin poisoning. However, immunotherapy has several disadvantages: (i) its efficacy is linked to it being rapidly administered since the antibodies cannot rescue the poisoned cells, they act only on extracellular ricin, and (ii) it appears to be relatively ineffective in the event of aerial or digestive poisoning, since the antibodies are unable to reach the affected pulmonary or digestive epithelium.

Studies based on the use of soluble receptor mimics for trapping ricin have also been carried out. This involves sugar derivatives (including dendrimers) that do not have an inhibitory effect greater than that of lactose alone (Rivera-Sagredo, A.; Solis, D.; Diaz-Mauriro, T.; Jimenez-Barbero, J.; Martin-Lomes, M. Eur. J. Biochem. 1991, 197, 217. and Dawson, R. M.; Alderton, M. R.; Wells, D.; Hartley, P. G. J. Appl. Toxicol. 2006, 26, 247).

Sugar derivatives as weak ricin inhibitors Inhibitors IC₅₀ (mM) 1

  Lactose 0.74 2

  Galactose 1.39 3 3rd-generation dendrimer. Terminal 1.16 sugars: galactoses 4 Dispersed linear polymer. Terminal 0.42-0.85 sugars: galactoses 5

  Galactose with anomeric lipid chain —

Other sugars carrying a water-insoluble lipid chain in the anomeric position have also been synthesized. They form a self-assembled lyotropic gel which is capable of sequestering ricin by means of the galactose-based surfactants.

A certain number of vaccines have been described in particular in patents by the US ARMY. They claim protection with respect to ricin via the administration of an immunogenic amount of RTA or RTB derivatives (U.S. Pat. No. 6,869,787).

However, a vaccine approach for countering the effects of ricin does not appear, at the current time, to be an effective response against this threat.

This is because only a few categories of individuals, identified as potentially exposed to ricin, could be preventively vaccinated. As things stand, it is not envisioned to vaccinate the population against this bioagent.

More recently, Haslam et al. (Saenz, J. B.; Doggett, T. A.; Haslam, D, B. Identification and Characterization of Small Molecules That Inhibit Intracellular Toxin Transport”, Infect. Immun. 2007, 75, 4552-4561) have described a high-throughput screening on a cell assay (Vero monkey kidney cells) for searching for ricin inhibitors, and have presented the following compounds:

The mode of action of these compounds is not specified, but these molecules appear to block the transport of the toxin inside the cells (endosomes and Golgi apparatus). However, these compounds, in particular compound A, which is a benzodiazepine derivative, have been tested and it has been noted that they do not protect A549 human pulmonary epithelial cells, unlike the compounds which are subjects of the present invention.

Thus, to date, these strategies have not made it possible to identify compounds capable of effectively protecting cells or animals exposed to ricin. The antibodies which are effective in the case of ricin injection are not affected in the case of inhalation or ingestion.

In conclusion, no specific treatment is yet available in humans for combating ricin poisoning.

In this perspective, the inventors have identified, by high-throughput screening, molecules capable of protecting cells in culture brought into contact with ricin. The mode of action of these compounds remains unknown even though they appear to act at the cellular level—and not directly on the toxin—probably by modifying one or more steps of the intracellular trafficking of ricin. Chemical optimization of these compounds has made it possible to progress to compounds having a greater cell protection capacity.

It should be emphasized that these compounds are the first inhibitors active on human pulmonary and digestive epithelial cells with respect to the toxic activity of ricin that have been identified to date.

Given that the compounds identified act at the cellular level by modifying the intracellular trafficking of ricin, these compounds may also be capable of blocking the internalization of other AB toxins and of viruses. This is because AB toxins and viruses (Sieczkarski, S. B., Whittaker, G. R. Dissecting virus entry via endocytosis, J. Gen. Virol. 2002, 83, 1535) exploit cellular trafficking pathways which are partly in common with those used by ricin. Thus, cell protection has been obtained with respect to diphtheria toxin and verotoxin-2 (Shiga-like toxin) in the presence of some of the compounds identified by screening.

The subject of the present invention is thus compounds having the property of protecting eukaryotic cells against the effects of toxins with intracellular activity, such as ricin, botulinum toxins, diphtheria toxins, anthrax toxins, cholera toxin, pertussis toxin, Shiga toxin (verotoxin-2) Escherichia coli thermolabile toxins, the major clostridial toxins, dermonecrotic factors and viruses which use the internalization pathway for infecting cells, for example RNA viruses, Flaviviridae (such as dengue or yellow fever), Orthomyxoviridae (such as the flu) or else Rhabdoviridae (such as rabies). This property is particularly advantageous since, during ricin poisoning via the respiratory route (inhalation) or by absorption (ingestion), these cells are the first that come into contact with the toxin.

Firstly, the invention relates to the use of compounds of general formula (I)

in which: Cy represents a group chosen from:

W is chosen from a hydrogen atom or a halogen atom, Y is chosen from a hydrogen atom or a hydroxyl function and Z is a carbon atom or a bond (Cy is then a noradamantyl nucleus), it being understood that, when Cy is an adamantyl nucleus, the chain

is attached thereto in position 1 or 2, p represents 0 or 1; X represents either:

-   -   a bond;     -   an optionally unsaturated, optionally branched, C₁-C₆ alkyl         chain which is optionally substituted with a phenyl radical, an         acid function and/or a C₁-C₃ alkyl ester radical; said chain         being optionally interrupted with an oxygen atom;

—CO—, —O—CO—, —CO—NH— or

R¹ represents a radical containing 1 to 21 carbon atoms, which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom; said radical being optionally monosubstituted or disubstituted with a halogen atom, a —COOH, —OH or —NO₂ function, a C₁-C₃ alkyl radical, a C₁-C₃ alkoxy radical or a C₁-C₃ acyloxy radical; R² either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C₁-C₃ alkyl radical, a C₂-C₄ acyl radical or the radical

it being understood that, when R² is a bond, then the nitrogen atom bearing R² and X or the adjacent carbon atom (when p=1) are linked by a double bond, it being understood that X, R¹ and R² can form, with the adjacent nitrogen atom, an imidazole, oxazole, triazole or benzimidazole ring, which is optionally partially saturated, such as in particular dihydroimidazole, optionally substituted with a phenyl or pyridine radical; and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition intended for the prevention and/or treatment of poisonings with at least one toxin with an intracellular mode of action or with at least one virus that uses the internalization pathway for infecting mammalian eukaryotic cells.

The invention also relates to the pharmaceutically acceptable salts of these compounds, such as hydrochlorides, hydrobromides, sulfurtes or bisulfurtes, phosphates or hydrogen phosphates, acetates, oxalates, benzoates, succinates, fumarates, maleates, lactates, citrates, tartrates, gluconates, methanesulfonates, benzenesulfonates and para-toluenesulfonates.

The term “halogen atom” is intended to mean the chemical elements of group VII of the Periodic Table of Elements, in particular fluorine, chlorine, bromine and iodine. The halogen atoms that are preferred for implementing the present invention are bromine (Br) and fluorine (F).

The term “C₁-C₃ alkyl chain or radical” denotes, respectively, a linear or branched hydrocarbon-based chain or radical; mention may be made, for example, of methyl, ethyl, propyl or isopropyl.

The term “C₁-C₃ alkoxy radical” is intended to mean an —OC_(n)H_(2n+1) radical, n being an integer between 1 and 3; mention may be made, for example, of the methoxy, ethoxy, propyloxy or isopropyloxy radical. Preferably, n is 1.

The term “C₁-C₃ acyloxy radical” is intended to mean an —O(CO)C_(n)H_(2n+1) or —(CO)OC_(n)H_(2n+1) radical, n being an integer between 1 and 3; mention may be made, for example, of the acetyl radical. Preferably, n is 1.

The term “C₁-C₃ acyl radical” is intended to mean a —(CO)C_(n)H_(2n+1) radical, n being an integer between 1 and 3.

According to one particular embodiment of the invention, the R¹ radical containing 1 to 21 carbon atoms, which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom, is chosen from: a linear or branched, saturated or unsaturated alkyl radical containing from 1 to 8 carbon atoms, a saturated or unsaturated cyclic radical containing 5 or 6 carbon atoms, a saturated or unsaturated bicyclic radical containing 9 or 10 carbon atoms, a saturated or unsaturated tricyclic radical containing 14 carbon atoms, a saturated or unsaturated heterocyclic radical containing 5 atoms, a saturated or unsaturated heterocycle containing 6 atoms, and a saturated or unsaturated biheterocyclic radical containing 9 or 10 atoms.

More specifically, the linear or branched, saturated or unsaturated alkyl radical containing from 1 to 8 carbon atoms is chosen from: a tert-butyl, 2,4,4-trimethylpentanyl, 3-hydroxy-2-methylpropanoate and hydroxymethylpropane-1,3-diol radical.

The cyclic radicals listed above are preferably chosen from the radicals: cyclopentylmethanol, cyclomethanoate, phenyl, cyclohexyl, pyridine, furan, thiophene, imidazole, quinoline, indole, benzofuran, adamantyl, naphthalene, anthracene, and the following cyclic radicals:

with W′ being —H or —COOC_(n)H2_(n+1), with n being between 1 and 3,

Preferably, the compounds of general formula (I) are such that R¹ is an optionally substituted phenyl radical and/or X is —CH₂— and/or R² is a hydrogen atom and/or W represents a Br atom.

According to one particular variant of the invention, the compounds of general formula (I) are such that R¹ is the radical:

in which:

-   -   R³ is chosen from a saturated or unsaturated cyclic radical         containing 5 or 6 carbon atoms; a saturated or unsaturated         bicyclic radical containing 9 or 10 carbon atoms; a saturated or         unsaturated tricyclic radical containing 14 carbon atoms; a         saturated or unsaturated heterocyclic radical containing 5         atoms; a saturated or unsaturated heterocyclic radical         containing 6 atoms; a saturated or unsaturated biheterocyclic         radical containing 9 or 10 atoms; said radicals being optionally         substituted with at least one halogen, —NO₂, —OH or one C₁-C₃         alkyl radical; the radicals are preferably chosen from the         radicals: phenyl, furan, indole and thiophene; and     -   R⁴ is chosen from —CO—O—, —N═CH— or —NH—CH₂—.

According to another variant of the invention, the compounds of general formula (I) are defined by general formula (I′):

where W, p, R³ and R⁴ are as defined above and X is either a bond or —CO—.

More particularly, the compounds of general formula (I) are chosen from:

1 N-benzyladamantylamine

2 N-{2-bromobenzyl)adamantylamine

3 N-(3-bromobenzyl)adamantylamine

4 N-(4-bromobenzyl)adamantylamine

5 N-(3-fluorobenzyl)adamantylamine

6 N-(3-hydroxybenzyl)adamantylamine

7 N-(2-methoxybenzyl)adamantylamine

8 N-(3-methoxybenzyl)adamantylamine

9 N-(4-methoxybenzyl)adamantylamine

10 N-(2-nitrobenzyl)adamantylamine

11 N-(4-nitrobenzyl)adamantylamine

12 N-(4-carbethoxybenzyl)adamantylamine

13 4-bromo-2-((1- adamantylino)methyl)phenol

14 N-(2-bromo-5- methoxybenzyl)adamantylamine

15 N-[(2-methoxy-5- bromo)benzyl]adamantylamine

16 N-((pyridin-2-yl)methyl)adamantylamine

17 N-((pyridin-3-yl)methyl)adamantylamine

18 N-((pyridin-4-yl)methyl)adamantylamine

19 N-((5-methylfuran-2- yl)methyl)adamantylamine

20 N-((5-methylthiophen-2- yl)methyl)cyclohexanamine

21 N-[{3-furyl)methyl]adamantylamine

22 N-((1-methyl-1H-imidazol-5- yl)methyl)adamantylamine

23 N-[(5-N- methylimidazolyl)methyl]adamantylamine

24 Benzo[d][1,3]dioxol-4- yl)methyl)adamantylamine

25 N-((5-nitrobenzo[d][1,3]dioxol-6- yl)methyl)adamantylamine

26 N-((quinolin-3-yl)methyl)adamantylamine

27 N-((quinolin-4-yl)methyl)adamantylamine

28 N-((1-methyl-1H-indol-2- yl)methyl)adamantylamine

29 N-phenethyladamantylamine

30 N-(3-phenylpropyl)adamantylamine

31 N-(2-(benzyloxy)ethyl)adamantylamine

32 N-cinnamyladamantylamine

33 N-methyl(3-bromobenzyl)adamantylamine

34 N-benzyl-2-adamantylamine

35 N-(2-bromobenzyl)-2-adamantylamine

36 N-(3-bromobenzyl)-2-adamantylamine

37 N-(4-bromobenzyl)adamantylamine

38 N-(2-fluorobenzyl)-2-adamantylamine

39 N-(3-fluorobenzyl)-2-adamantylamine

40 N-(4-fluorobenzyl)-2-adamantylamine

41 N-(3-hydroxybenzyl)-2-adamantylamine

42 N-(2-methoxybenzyl)-2-adamantylamine

43 N-(3-methoxybenzyl)-2-adamantylamine

44 N-(4-methoxybenzyl)-2-adamantylamine

45 N-(2-nitrobenzyl)-2-adamantylamine

46 N-(4-nitrobenzyl)-2-adamantylamine

47 N-(4-carbethoxybenzyl)-2- adamantylamine

48 4-bromo-2-((2- adamantylamino)methyl)phenol

49 N-(2-bromo-5-nitrobenzyl)-2- adamantylamine

50 N-(5-bromo-2-methoxybenzyl)-2- adamantylamine

51 N-(5-fluoro-2-nitrobenzyl)-2- adamantylamine

52 N-(2,5-difluorobenzyl)-2-adamantylamine

53 N-((pyridin-2-yl)methyl)-2- adamantylamine

54 N-((pyridin-3-yl)methyl)-2- adamantylamine

55 N-((pyridin-4-yl)methyl)-2- adamantylamine

56 N-((5-methylfuran-2-yl)methyl)-2- adamantylamine

57 N-((5-methylthiophen-2-yl)methyl)-2- adamantylamine

58 N-((furan-3-yl)methyl)-2-adamantylamine

59 N-((1-methyl-1H-imidazol-5-yl)methyl)-2- adamantylamine

60 N-[(5-N-methylimidazolyl)methyl]-2- adamantylamine

61 Benzo[d][1,3]dioxol-4-yl)methyl)-2- adamantylamine

62 N-((5-nitrobenzo[d][1,3]dioxol-6- yl)methyl)-2-adamantylamine

63 N-((quinolin-3-yl)methyl)-2- adamantylamine

64 N-((quinolin-4-yl)methyl)-2- adamantylamine

65 N-((1-methyl-1H-indol-2-yl)methyl)-2- adamantylamine

66 N-(1-(3-bromophenyl)ethyl)-2- adamantylamine

67 N-benzhydryl-2-adamantylamine

68 N-(2-(benzyloxy)ethyl)-2-adamantylamine

69 N-{phenylpropyl)-2-adamantylamine

70 N-(1-phenylethyl)-2-adamantylamine

71 N-(1-(pyridin-2-yl)ethyl)-2- adamantylamine

72 N-(2-adamantylmethyl)-1- (adamantyl)ethanamine

73 N-methyl(3-bromobenzyl)-2- adamantylamine

74 N-(3-bromobenzyl)-2-methylpropan-2- amine

75 N-(3-bromobenzyl)-2,4,4-trimethylpentan- 2-amine

76 2-(3-bromobenzylamino)-3-hydroxy-2- methylpropanoic acid

77 2-(3-bromobenzylamino)-2- (hydroxymethyl)propane-1,3-diol

78 N-(3-bromobenzyl)cyclohexanamine

79 4-(3-bromobenzylamino)cyclohexanol

80 N-(3-fluorobenzyl)cyclohexylamine

81 4-(3-fluorobenzylamino)cyclohexanol

82 (1-(3- bromobenzylamino)cyclopentyl)methanol

83 1-(3- bromobenzylamino)cyclopentanecarboxylic acid

84 N-(3-bromobenzyl)bicyclo[2.2.1]heptan-2- amine

85 2-(3- bromobenzylamino)bicyclo[2.2.1]heptane- 2-carboxylic acid

86 N-(3-bromobenzyl)noradamantylamine

87 N-(3-bromobenzyl)-1-hydroxy-2- adamantylamine

88 N-(3-bromobenzyl]-N- ((benzo[d][1,3]dioxol-6-yl)methyl)(3- bromophenyl)methanamine

89 2-(3-bromobenzylamino)-2-(4- hydroxybenzyl)propanoic acid

90 2-(3,4-dihydroxybenzyl)-2-(3- bromobenzylamino)propanoic acid

91 2-(3-bromobenzylamino)-2- phenylbutanoic acid

92 2-(3-bromobenzylamino)-2,2- diphenylacetic acid

93 methyl 2-(3-bromobenzylamino)-2-methyl- 3-phenylpropanoate

94 methyl 3-(3-bromobenzylamino)-8- azabicyclo[3.2.1]octane-8-carboxylate

95 N-(3-bromobenzyl)-9-methyl-9- azabicyclo[3.3.1]nonan-3-amine

96 N-(3-bromobenzyl)benzo[d][1,3]dioxol-5- amine

97 2-(3-bromobenzylideneamino)-2-(3,4- dihydroxyphenyl)propanoic acid

98 N-benzyl(3-bromophenyl)methanamine

99 bis(3-bromobenzyl)amine

100 N-(3-fluorobenzyl)(3- bromophenyl)methanamine

101 N-(3-bromobenzyl)(1-methyl-1H-indol-2- yl)methanamine

102 N-(3-bromobenzyl)-1-phenylethanamine

103 N-(3-bromobenzyl)-1-(3- bromophenyl)ethanamine

104 N-(3-bromobenzyl)-1-(pyridin-2- yl)ethanamine

105 N-(3-bromobenzyl)quinuclidin-3-amine

106 (1R*,5S*)-N-(3- bromobenzyl)bicyclo[3.3.1]nonan-9-amine

107 N-(3-bromobenzyl)-8-methyl-8-aza- bicyclo[3.2.1]octan-3-amine

108 N-(1-(3- bromophenyl)ethyl)adamantylamine

109 N-(3-fluorobenzyl)noradamantylamine

110 N-(3-bromobenzyl)adamantylamine hydrochloride salt

111 N-(5-bromo-2- methoxybenzyl)adamantylamine hydrochloride salt

112 N-(2-bromobenzyl)-2-adamantylamine hydrochloride salt

113 (E)-N-(3- bromobenzylidene)adamantylamine

114 (E)-N-(3- fluorobenzylidene)adamantylamine

115 (E)-N-((1-methyl-1H-indol-2- yl)methylene)adamantylamine

116 (E)-N-benzylideneadamantylamine

117 (E)-N-(3- bromobenzylidene)adamantylamine

118 (E)-N-(3- fluorobenzylidene)adamantylamine

119 (E)-N-(3- bromobenzylidene)noradamantylamine

120 (E)-N-((1-methyl-1H-indol-2- yl)methylene)noradamantylamine

121 N-1-adamantylbenzamide

122 N-2-adamantylbenzamide

123 phenyl N-adamantylcarbamate

124 N-adamantyl benzenesulfonamide

125 N-adamantyl-N-(3- bromobenzyl)acetamide

126 phenyl N-2-adamantylcarbamate

127 N-adamantyl-N-(3- bromobenzyl)benzamide

128 N-2-adamantyl benzenesulfonamide

129 1-(adamantyl)-3-phenylurea

131 1-(adamantyl)-1-(3-bromobenzyl)-3- phenylurea

132 1-(2-adamantyl)-3-phenylurea

134 1-(adamantyl)-2,5-dihydro-1H-imidazole

135 1-(adamantyl)-2,5-dihydrooxazole

136 1-(adamantyl)-1-phenyl-4,5-dihydro-1H- imidazole

137 1-(adamantyl)-3a,4,5,6,7,7a-hexahydro- 1H-benzo[d]imidazole

138 N-(3-chlorobenzyl)adamantylamine

139 N-(3-chlorobenzyl)-2-adamantylamine

140 N-(3-iodobenzyl)-2-adamantylamine

141 N-(2,2-diphenylethyl)-2-adamantylamine

142 N-(naphthalen-1-ylmethyl)-2- adamantylamine

143 N-(phenanthren-9-ylmethyl)-2- adamantylamine

144 4-((adamantylamino)methyl)benzoic acid

145 adamantylamino-4-phenyl-1H-1,2,3- triazole

146 adamantylamino-4-phenyl-1H-1,2,3- triazole

147 2-(adamantylamino-1H-1,2,3-triazol-4- yl)pyridine

148 N-(2-bromo-5- nitrobenzyl)adamantylamine

149 2-(3-bromobenzylideneamino)-N- phenylbenzamide

150 2-(3-bromobenzylamino)-N- phenylbenzamide

151 2-(3-fluorobenzylideneamino)-N- phenylbenzamide

152 (E)-2-((furan-2-yl)methyleneamino)-N- phenylbenzamide

153 (E)-2-((furan-3-yl)methyleneamino)-N- phenylbenzamide

154 (E)-2-((5-methylfuran-2- yl)methyleneamino)-N-phenylbenzamide

155 (E)-2-(5-fluoro-2-nitrobenzylideneamino)- N-phenylbenzamide

156 (E)-2-(4-fluorobenzylideneamino)-N- phenylbenzamide

157 (E)-2-(2-fluorobenzylideneamino)-N- phenylbenzamide

158 (E)-2-((1-methyl-1H-indol-2- yl)methyleneamino)-N-phenylbenzamide

159 (E)-2-(5-bromo-2- hydroxybenzylideneamino)-N- phenylbenzamide

160 2-(2-fluorobenzylamino)-N- phenylbenzamide

161 (E)-2-(2-(5-methylthiophen-2-yl)vinyl)-N- phenylbenzamide

191 N-cinnamyl-2-adamantylamine

192 N-(3-nitrobenzyl)-2-adamantylamine

The present invention also relates to the compounds of general formula (I) as defined above and the pharmaceutically acceptable salts thereof as such, except for compounds 1, 6, 8, 11, 18, 29, 30, 34, 74, 78, 98, 100, 113, 114, 116, 121, 122, 124, 128, 135, 145 and 161.

The compounds which are aminoadamantane derivatives were prepared by reductive amination according to the reaction which follows:

Specifically, the invention relates to the process for preparing the compounds of general formula (Ia):

in which:

-   -   Cy is the adamantyl nucleus with the nitrogen atom in position 1         or 2;     -   X represents a branched, optionally unsaturated, C₁-C₃ alkyl         chain which is optionally interrupted with an oxygen atom;     -   R¹ is a radical containing from 1 to 21 carbon atoms which is         optionally branched or cyclic, and saturated or unsaturated, in         which one or more of the carbon atoms can be replaced with a         nitrogen, oxygen and/or sulfur atom, and which is optionally         monosubstituted or disubstituted with a halogen atom, an —OH or         —NO₂ function, a C₁-C₃ alkoxy radical or a C₁-C₃ acyloxy         radical;     -   R² is chosen from —H or a C₁-C₃ alkyl radical, characterized in         that it comprises the following steps:     -   adding a suspension of 1-adamantylamine or 2-adamantylamine in         methanol, with stirring, to an aromatic aldehyde chosen         according to the compound of general formula (Ia) to be         prepared, in the presence of BH₃CN on resin and of acetic acid;     -   stirring the mixture for 2 days at ambient temperature.

In a more detailed manner, the compounds of general formula (Ia) which appear in tables A1 and A2 according to example 1 are prepared in methanol by treatment of 1-adamantylamine (for the compounds of table A1) or of 2-adamantylamine (for the compounds of table A2) in the presence of an aromatic aldehyde (1 equiv.) according to the compound to be prepared. Supported cyanoborohydride is used (BH₃CN on resin, 1.5 equiv.) as reducing agent in the presence of acetic acid (3 equiv.). The whole is stirred for 2 days at ambient temperature, filtered, washed with methanol, evaporated, and then purified according to methods known to those skilled in the art.

This same process makes it possible to prepare the derivatives of general formula (Ib):

in which:

-   -   —Cy is

-   -   X represents a branched, optionally unsaturated, C₁-C₃ alkyl         chain which is optionally interrupted with an oxygen atom, —CO—,         —CO—NH—, —CS—NH— or

-   -   R² is chosen from nothing, —H, —CH₃ or

it being understood that, when R² is nothing, then the nitrogen atom and X are linked by a double bond.

The invention therefore also relates to a process for preparing the compounds of general formula (Ib), characterized in that it comprises the following steps:

-   -   adding a suspension of 3-bromobenzylamine in methanol, with         stirring, to an aromatic aldehyde chosen according to the         compound of general formula (Ib) to be prepared, in the presence         of BH₃CN on resin and of acetic acid;     -   stirring the mixture for 2 days at ambient temperature.

In a more detailed manner, the compounds (Ib) that appear in table A3 and in table A4 are prepared by adding, with stirring, a suspension of an amine (1 equiv.) chosen according to the compound to be prepared (see tables A3 and A4 according to example 1) in methanol to an aldehyde (1 equiv.) for the compounds of table A3 or of 3-bromobenzylamine (1 equiv.) and an aldehyde in order to obtain the compounds of table A4, in the presence of 1.5 equiv. of BH₃CN on resin and of acetic acid (3 equiv.). The whole is stirred for 2 days at ambient temperature, filtered, washed with methanol, evaporated, and then purified according to methods known to those skilled in the art.

The formation of the salts is carried out by treatment of the amine compound (corresponding to the desired salt) in CH₂Cl₂ with a solution of the corresponding acid in a solvent (for example, HCl in ether).

The precipitate is filtered off and dried under vacuum so as to give the salt of the acid (for example, hydrochloride in the case of HCl). They appear in table B of example 1.

The 1-aminoadamantane, 2-aminoadamantane or noradamantylamine derivatives of general formula (Ic)

in which:

-   -   —Cy is

with Z being a carbon atom or nothing (noradamantyl nucleus), with the nitrogen atom in position 1 or 2 when Cy is the adamantyl nucleus;

-   -   R¹ is chosen from a phenyl radical, a heterocyclic radical such         as the pyridine, furan, thiophene, quinoline or indole radicals,         preferably the indole radical, said radical being optionally         monosubstituted or disubstituted with a halogen atom, an —OH or         —NO₂ function, a C₁-C₃ alkoxy radical or a C₁-C₃ acyloxy         radical, a C₁-C₃ alkyl radical, preferably a methyl radical;         are prepared as follows: a stirred suspension, in methanol, of         1-, 2- or noradamantylamine (1 equiv.) is added to an aldehyde         (1 equiv.) chosen according to the compound to be prepared (see         tables C1, C2 and C3 of example 1). The whole is mixed for two         days at ambient temperature and then evaporated.

Thus, the invention relates to the process for preparing the 1-aminoadamantane, 2-aminoadamantane or noradamantylamine derivatives of general formula (Ic), characterized in that it comprises the following steps:

-   -   stirring a suspension, in methanol, of 1-, 2- or         noradamantylamine (1 equiv.);     -   adding to an aldehyde (1 equiv.) chosen according to the         compound to be prepared;     -   mixing the whole for two days at ambient temperature and then         evaporating.

The preparation of the imines is carried out by adding a solution of the amine in MeOH to the aldehyde, the amine and the aldehyde being chosen according to the imine to be prepared, and stirring the mixture for 2 days. After evaporation and purification, the imines are obtained.

The imines are reduced as follows: BH₃CN on resin (3 equiv.) and AcOH are added to a solution of the imine in MeOH. After 3 days at ambient temperature, the mixture is filtered, washed with methanol, and then concentrated under vacuum. The resulting crude compound is purified according to conventional methods.

The invention also relates to a process for preparing the imines of general formula (I), characterized in that it comprises the following steps:

-   -   adding a solution of amine in MeOH to an aldehyde, said amine         and said aldehyde being chosen according to the compound of         general formula (I) to be prepared;     -   stirring the mixture for 2 days;     -   evaporating and purifying.

The invention also relates to a process for preparing a reduced imine of general formula (I), characterized in that it comprises the following steps:

-   -   adding BH₃CN on resin (3 equiv.) and AcOH to a solution of the         imine obtained according to the above process, in MeOH;     -   treating for 3 days at ambient temperature;     -   filtering the mixture;     -   washing with methanol;     -   concentrating under vacuum.

The N-1-adamantylbenzamide and N-2-adamantylbenzamide compounds are prepared from the corresponding amines (1- or 2-adamantylamine (1 equiv.)) via treatment with a base such as NaH (1.1 equiv.) in DMF then addition of benzoyl chloride (1.2 equiv.) at 0° C. The mixture is stirred for 24 hours at ambient temperature, evaporated, and then washed with cyclohexane.

Finally, the invention relates to a process for preparing the N-1-adamantylbenzamide and N-2-adamantylbenzamide compounds comprising the following steps:

-   -   adding 1- or 2-adamantylamine and benzoyl chloride, at 0° C., to         a suspension of NaH in DMF;     -   stirring the mixture for 24 hours at ambient temperature.

Formation of Ureas

The invention also relates to a process for preparing a urea derivative of general formula (I), characterized in that it comprises the following steps:

-   -   adding, at 0° C., the isocyanate, the amine and the isocyanate         corresponding to said desired urea derivative (1.1 equiv.) to a         suspension of the amine which is a 1-adamantyl derivative (1         equiv.) in THF,     -   stirring the mixture for 24 hours at ambient temperature,     -   evaporating and purifying on a small silica cartridge.

Alkylation of Alcohols (for Example, Adamantane-Methanol)

The alcohols are firstly treated with iodine (2.5 equiv.) and a base such as potassium carbonate in tert-butanol and are heated for 24 h at 70° C. The nucleophile (amine, alcohol) is then added (1.5 equiv.). After conventional treatment and purification, the alkylated compounds are obtained.

Formation of the Triazole Derivatives by Click Chemistry

The invention also relates to a process for preparing triazole derivatives of general formula (I), characterized in that it comprises the following steps:

-   -   reacting an azide with an acetylenic compound (1.1 equiv.),         these two reactants being chosen according to said triazole         compound of general formula (I) to be synthesized, in the         presence of copper on carbon (catalytic) and triethylamine (1.0         equiv.) in dioxane for 24 h at ambient temperature;     -   filtering the mixture through celite and evaporating;     -   purifying.

The invention also relates to 2-amino-N-phenylbenzamide as synthesis intermediate for the amines of general formula (I).

The present invention also relates to the use of compounds which are benzodiazepine derivatives of general formula (II):

where A and B represent a carbon atom or a nitrogen atom with the proviso that, if A=N then B=C, and if A=C then B=N; R³ is chosen from a hydrogen or halogen atom; a C₁-C₆ alkyl radical, a C₁-C₆ alkoxy radical or a C₁-C₆ acyloxy radical, these radicals being optionally substituted with a C₁-C₆ alkoxy radical; an aryloxy radical or a heteroaryloxy radical; R⁴ either represents a bond or is chosen from a hydrogen atom, a C₁-C₃ acyloxy radical, a C₁-C₃ alkoxy radical or a phenyl; R⁵ either represents a bond or is chosen from a hydrogen atom; a C₁-C₃ alkyl radical; a C₁-C₃ alkoxy radical; a C₁-C₃ acyloxy radical or a phenyl radical which is optionally substituted with an —OH function and/or a halogen atom, a C₁-C₃ alkyl radical, a C₁-C₃ alkoxy radical, a C₁-C₃ acyloxy radical, an —NO₂ or —CF₃ function, or a radical

it being understood that R₄ and R₅ cannot simultaneously represent a bond and that, when one of the two is a bond, then A and B are linked by a double bond; and that, when B is a carbon atom, R⁵ can also form, with the hydrogen atom borne by the carbon adjacent to B, a ring of 5 or 6 atoms, optionally substituted with a phenyl radical, optionally interrupted with a nitrogen, sulfur or oxygen atom; preferably, it is a ring containing 5 atoms, interrupted with an oxygen atom; for the preparation of a pharmaceutical composition intended for the prevention and/or treatment of poisonings with at least one toxin with an intracellular mode of action or with at least one virus that uses the internalization pathway for infecting mammalian eukaryotic cells.

The invention also relates to the pharmaceutically acceptable salts of these compounds.

The term “C₁-C₆ alkyl radical” denotes a linear or branched hydrocarbon-based radical containing from 1 to 6 carbon atoms; mention may be made, for example, of methyl, ethyl, propyl, or isopropyl.

The term “C₁-C₆ alkoxy radical” is intended to mean an —OC_(m)H_(2m+1) radical, m being an integer between 1 and 6.

The term “C₁-C₆ acyloxy radical” is intended to mean an —O(CO)C_(m)H_(2m+1) or —(CO)OC_(m)H_(2m+1) radical, m being an integer between 1 and 6.

The term “aryloxy radical” is intended to mean an aryl group linked to the rest of the compound by an oxygen atom.

The term “heteroaryloxy radical” is intended to mean a heteroaryl group linked to the rest of the compound by an oxygen atom.

Preferably, the compounds of general formula (II) are such that R³ is a bond and/or R⁴ represents a hydrogen atom and/or R⁵ represents a phenyl radical and/or, when A is a carbon atom, then R⁴ is a phenyl radical, and/or, when B is a carbon atom, then R⁵ is a phenyl radical.

More particularly, the compounds of general formula (II) are chosen from:

162 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2- one

163 7-bromo-5-phenyl-2,3-dihydro-1H-1,4- benzodiazepin-2-one

164 7-bromo-5-phenyl-2,3,4,5-tetrahydro-1H-1,4- benzodiazepin-2-one

165 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2- one

166 4-phenyl-2,3,4,5-tetrahydro-1H-1,5- benzodiazepin-2-one

167 4,5-dihydro-7-methoxy-5-phenyl-1H- benzo[e][1,4]diazepin-2(3H)-one

168 Ethyl 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1H- 1,5-benzodiazepine-1-carboxylate

169 5-phenyl-2,3,4,5-tetrahydro-1H-1,4- benzodiazepin-2-one

170 7-chloro-5-phenyl-2,3-dihydro-1H-1,4- benzodiazepin-2-one

171 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-1,4- benzodiazepin-2-one

172 4-(2-hydroxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

173 4-(5-bromo-2-hydroxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

174 4-(5-fluoro-2-hydroxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

175 8-bromo-3-phenyl-3,3a,5,10- tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepin- 4(2H)-one

176 4-m-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one

177 4-(3-methoxyphenyl)-1H- benzo[b][1,4]diazepin-2{3H)-one

178 4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin- 2(3H)-one

179 4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin- 2(3H)-one

180 4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin- 2(3H)-one

181 4-(3-(trifluoromethyl)phenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

182 7-bromo-4-m-tolyl-1H-benzo[b][1,4]diazepin- 2(3H)-one

183 7-bromo-4-(3-methoxyphenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

184 7-bromo-4-(3-nitrophenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

185 7-bromo-4-(3-chlorophenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

186 7-bromo-4-(3-bromophenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

187 7-bromo-4-(3-(trifluoromethyl)phenyl)-1H- benzo[b][1,4]diazepin-2(3H)-one

193 7-bromo-6-phenyl-4-propionyl-4,5-dihydro-1H- benzo[e][1,4]diazepin-2(3H)-one

The present invention also relates to the compounds of general formula (II) and the pharmaceutically acceptable salts thereof as such, except for compounds 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193.

The synthesis of the compounds of general formula (II) according to the invention is described in example 1.

More particularly, the benzo[e][1,4]diazepine derivatives and the benzo[b][1,4]diazepine derivatives of general formula (II) are prepared as follows:

-   -   addition to a suspension of diamine, chosen according to the         compound to be prepared, for example from benzene-1,2-diamine or         4-bromobenzene-1,2-diamine (1 equiv.) in toluene (2 ml) with a         β-keto ester (1 equiv.);     -   stirring of the mixture at reflux (120° C.) for 3 hours;     -   dilution of the mixture in EtOAc, acidification (pH 5) and         extraction with EtOAc;     -   filtration, evaporation, and washing with Et₂O.

The invention also relates to the compounds which are of use as synthesis intermediates for the compounds of general formula (II), chosen from: tert-butyl N-[(phenylcarbamoyl)methyl]carbamate, tert-butyl(4-methoxyphenylcarbamoyl)methylcarbamate, 2-amino-N-phenylacetamide, 2-amino-N-(4-methoxyphenyl)acetamide and 2-benzoyl-4-bromoaniline.

The compounds according to the invention are pharmacologically active substances and are of value by virtue of their inhibitory effect on toxins with an intracellular mode of action, in particular on ricin.

According to another of its subjects, the invention relates to the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof except for compounds 1, 6, 8, 11, 18, 29, 30, 34, 74, 78, 98, 100, 113, 114, 116, 121, 122, 124, 128, 135, 145, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193, for use as a medicament, in particular as an active ingredient.

The invention also relates to pharmaceutical compositions or medicaments comprising one or more compounds of general formula (I) or (II) and the pharmaceutically acceptable salts thereof except for compounds 1, 6, 8, 11, 18, 29, 30, 34, 74, 78, 98, 100, 113, 114, 116, 121, 122, 124, 128, 135, 145, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193, in a pharmaceutically acceptable vehicle.

The term “pharmaceutically acceptable” is intended to mean compatible with administration to an individual, preferably a mammal, by any route of administration.

Those skilled in the art will be capable of adapting the formulation of the compounds of general formulae (I) and (II) according to their physicochemical properties and their route of administration.

The medicament may be administered by the oral, parenteral, pulmonary, ocular, nasal, etc., route. The modes of administration of the compounds (I) and (II) that are preferred are those which use the aerial (inhalation), oral (ingestion), parenteral or local (topical) routes.

The amount of compound of formula (I) or (II) to be administered to the mammal depends on the actual activity of this compound, it being possible for said activity to be measured by means which are disclosed in the examples. This amounts also depends on the seriousness of the pathological condition to be treated, in particular on the amount of ricin absorbed and on the route via which it was absorbed; finally, it depends on the age and the weight of the individual to be treated.

The use of the compounds of general formula (I) or (II) is particularly advantageous for preventing and/or treating disorders caused by AB toxins with an intracellular mode of action and viruses that use the internalization pathway for infecting cells.

More specifically, the AB toxins or toxins with an intracellular mode of action are in particular: ricin, botulinum toxins, diphtheria toxins, anthrax toxins, cholera toxin, pertussis toxin, Shiga toxin (verotoxin-2), Escherichia coli thermolabile toxins, the major clostridial toxins, and dermonecrotic factors; examples of these toxins are listed in the table below:

Molecular Toxin Origin* Enzymatic activity target Class A/B toxins Diphtheria toxin (DT) C. diphtheriae (+) ADP- Elongation Exotoxin A (ETA) P. aeruginosa (−) ribosyltransferase factor 2 Botulinum toxins (NTBo C. Botulinum (+) Zinc-endopeptidase SNARE Neurotoxins A/G) proteins Tetanus toxin (NTTe) C. tetani (+) Lethal toxin (LT) C. sordellii (+) Glucosyltransferase Ras/Rho High- Hemorragic toxin (HT) proteins molecular- Toxin A (Tox A) C. difficile (+) weight toxins Toxin B (Tox B) α-toxin (α-Tox) C. novyi (+) Dermonecrotic toxin (DNT) B. pertussis (−) Deamidase Rho Dermonecrotic Cytotoxic necrotizing E. coli (−) proteins toxins factor type 1 and 2 (CNF1/2) Ab [illegible] Cholera toxin (CT) V. cholerae (−) ADP- Gsα toxins Thermolabile toxins (LT) E. coli (−) ribosyltransferase protein Pertussis toxin (PTX) B. pertussis (−) Gsα protein Shiga toxins S. dysenteriae (−) Ribonuclease 28S rRNA Shiga family Shiga-like toxins E. coli (−) toxins A [illegible] Edema toxin B. anthracis (+) Adenylate cyclase Calmodulin Anthrax toxins (edema factor EF + toxins protective antigen PA) Lethal toxin Zinc-endopeptidase MAP (lethal factor LF + kinases protective antigen PA) C2 toxin (C2I + C2II) C. botulinum (+) ADP- Actin Actin ADP- Iota toxin (Ia + Ib) C. perfringens (+) ribosyltransferase ribosylating Spiroform toxin (Sa + Sb) C. spiroforme (+) toxins CDT toxin (CDTa + CDTb) C. difficile (+) VIP toxin (VIP1 + VIP2) B. cereus (−) *Between parentheses, Gram staining Various Activities, Molecular Targets and Structures of the Main Bacterial Toxins with an Intracellular Action

The viruses that use the internalization pathway for infecting cells, hereinafter also denoted viruses, are, for example, RNA viruses, Flaviviridae (such as dengue or yellow fever), Orthomyxoviridae (such as the flu) or else Rhabdoviridae (such as rabies).

This use proves to be effective whether the individual touches, ingests or inhales the toxin or the virus, or else whether the toxin or the virus is injected into said individual.

Thus, these compounds may be used for the preparation of a pharmaceutical composition intended for treating the effects of AB toxins or toxins with an intracellular mode of action and of viruses that use the internalization pathway for infecting cells.

Concretely, a toxin such as ricin, when it is inhaled, produces signs of ocular irritation (burning sensation, watering of the eyes, more or less severe conjunctivitis) and pharyngeal irritation and also a more or less marked respiratory irritation: cough, dyspnea, pulmonary edema which can result in acute respiratory distress syndrome (ARDS). It should be noted that there is a risk of anaphylactic reaction. The lethal dose is 1 mg/kg (Ministry of Health, France).

Thus, the invention relates to the use of a compound of general formula (I) or (II), for the preparation of a pharmaceutical composition intended for protection against the effects of ricin, of other AB toxins and of viruses that use the internationalization pathway for infecting eukaryotic cells, especially epithelial, ocular, pharyngeal, tracheal, bronchial, skin or muscle cells, in particular pulmonary and digestive, preferably intestinal, epithelial cells, of mammals, preferably of humans.

The invention relates more specifically to the use of the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin; preferably, the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof are chosen from compounds 1, 3, 5, 9, 15, 19, 24, 28, 34, 36, 39, 59, 65, 67, 68, 69, 75, 86, 89, 105, 106, 109, 110, 111, 112, 117, 118, 122, 128, 131, 138, 139, 140, 142, 143, 148, 154, 161 and 193.

According to one preferred variant, the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.1):

in which: Cy represents a group chosen from:

Z is a carbon atom or a bond (Cy is then a noradamantyl nucleus), it being understood that, when Cy is an adamantyl nucleus, the nitrogen atom is attached thereto in position 1 or 2, R¹ represents:

-   -   a phenyl ring, optionally substituted with an —OCH₃ radical in         the para-position with respect to the carbon atom bonded to the         —CH₂—NH-Cy chain; said ring being alternatively optionally         substituted with a halogen atom in the meta-position with         respect to the carbon atom bonded to the —CH₂—NH-Cy chain, and         in this case, said ring optionally bears a second substitution         in the para-position with respect to said halogen atom, said         second substitution being chosen from —NO₂ and —OCH₃;     -   an indole, imidazole or furan ring substituted with a methyl         radical;     -   a benzo(1,3)dioxolo ring, a naphthalenyl ring or a phenanthrenyl         ring;         and the pharmaceutically acceptable salts thereof,         for the preparation of a pharmaceutical composition for         preventing and/or treating poisoning with ricin toxin.

Preferably, the compounds of general formula (I.1) are chosen from compounds 1, 3, 5, 9, 15, 19, 24, 28, 34, 36, 39, 59, 65, 86, 109, 110, 111, 112, 138, 139, 140, 142, 143 and 148.

According to another preferred variant, the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.2):

in which X represents —(CH₂)₂—O—CH₂—, —(CH₂)₃—, —CO— or —SO₂—, and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin.

Preferably, the compounds of general formula (I.2) are chosen from compounds 68, 69, 122 and 128.

According to yet another preferred variant, the invention relates to the use of compounds of general formula (I) which are defined by general formula (I.3):

in which W represents a halogen atom, and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin.

Preferably, the compounds of general formula (I.3) are chosen from compounds 117 and 118.

Another preferred variant of the invention relates to the use of the compounds of general formula (I.4):

in which Y is O or S, and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with ricin toxin.

Preferably, the compounds of general formula (I.4) are chosen from compounds 154 and 161.

The present invention also relates to the use of the compounds of general formulae (I) and (II) and the pharmaceutically acceptable salts thereof, for the preparation of a pharmaceutical composition for preventing and/or treating poisoning with diphtheria toxin.

The compounds suitable for the prevention and/or treatment of poisoning with diphtheria toxin are in particular those of general formula (I.5):

in which: Cy represents a group:

to which the nitrogen atom is attached in position 1 or 2, W and W′ are, independently of one another, chosen from a hydrogen atom, a halogen atom and a C₁-C₃ alkoxy radical, and the pharmaceutically acceptable salts thereof.

Preferably, the compounds of general formula (I.5) are chosen from compounds 5, 9, 39, 110, 111, 112, 139 and 140.

In addition to the above arrangements, the invention also comprises other arrangements which will emerge from the description that follows, which refer to examples of implementation of the present invention, and also to the appended figures in which:

FIG. 1 is a diagrammatic representation of the high-throughput cell assay.

FIG. 2 represents the results of the screening. The yellow dots (horizontal cloud of dots on the upper part of the graph) represent the positive controls (cells with ricin+lactose), the green dots (horizontal cloud of dots on the lower part of the graph) represent the negative controls (cells treated with ricin alone) and, in red, are the compounds according to the invention tested in the presence of ricin.

EXAMPLE 1 Examples of Synthesis of Compounds According to the Invention

The commercial reactants were purchased from Sigma-Aldrich and were used without prior purification. All the reactions were carried out under nitrogen with freshly distilled dry solvents and oven-dried glassware.

The purification methods used for preparing the compounds are specified in the “Purification method” column of the tables and coded as follows:

1: Filtration

2: Short pad (small column with silica already packaged) 3: Silica gel chromatography column

4: HPLC 5: Crystallization

6: Aqueous treatment then separation.

The ¹H NMR was carried out with a Brucker Advance 400 MHz instrument with a BBO probe. The solvents are specified for each experiment. The chemical shifts are given in parts per million (ppm), relative to the internal reference (TMS). The data are listed in the following order: δ, chemical shift; multiplicity (with s singlet, d doublet, t triplet, q quadruplet, m, multiplet), integration, coupling constants (J in Hertz, Hz).

The LC/MS analyses were carried out by HPLC (High Pressure Liquid Chromatography) coupled with a Waters® Autopurif mass spectrometer.

The ionization is obtained either by electron impact or by electrochemical ionization.

The data are obtained in m/z form.

Column: Xbridge C18 3-5 μM, 4.6 mm×100 mm

Flow rate: 1 ml/min

Detectors:

-   -   Waters 2996 photodiode array detector: UV (200-400 nm),     -   PL-ELS 1000,     -   MS ZQ 2000.

Injection volume: 1 μl with the Waters 2767 autosampler.

Method: 95% solution A (99.99% water, 0.01% formic acid), 5% B (100% acetonitrile) to 0% A, 100% B on a gradient of 8 minutes, then 5-minute stage.

The column chromatographies were carried out with a

Merck silica gel (particle size: 230-400 mesh). All the reactions were monitored by thin-layer chromatography with plates precoated with 0.2 mm-thick silica gel 60G-264 (Merck). Developing was carried out with a UV lamp or with diode.

Process A

The 1-aminoadamantane and 2-aminoadamantane derivatives of general formula (Ia) as described above and which appear, respectively, in tables A1 and A2 are prepared as follows: a suspension, in methanol, of 1-adamantylamine or 2-adamantylamine (0.5 mmol; 75 mg; 1 equiv.) is added, with stirring, to an aromatic aldehyde (1 equiv.) according to the compound to be prepared, in the presence of BH₃CN on resin (0.75 mmol; 1.5 equiv.) and of acetic acid (1.5 mmol; 84 μl; 3 equiv.). The whole is stirred for 2 days at ambient temperature, filtered, washed with methanol, evaporated and then purified.

Tables A1 and A2 give the number of the compound, the aldehyde used, the name of the compound obtained, the characteristics of the compound and also the code of the purification method used, the appearance of the compound obtained and its yield.

TABLE A1 Compounds which are 1-aminoadamantane derivatives, prepared by process A starting from 1- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 1 Benzaldehyde N-benzyladamantylamine ¹H NMR (CDCl₃, 1 400 MHz): δ 7.39 (m, 2H), white solid 7.32 (m, 3H), 3.86 (s, 2H), 100% 3.66 (bs, 1H), 2.12 (s, 3H), 1.84-1.63 (m, 12H). ESI + MS: calcd for C₁₇H₂₃N: 241.18; found: 242.2 (MH⁺) 2 2-bromobenzaldehyde N-(2- 1 bromobenzyl)- yellow solid adamantylamine 24% 3 3-bromobenzaldehyde N-(3- ¹H NMR (CDCl₃, 1 bromobenzyl)- 400 MHz): δ 7.56 (s, 1H), white solid adamantylamine 7.39 (d, 1H, J = 6.7 Hz), 35% 7.33 (d, 1H, J = 7.6 Hz), 7.18 (t, 1H, J = 8 Hz), 6.09 (bs, 1H), 3.81 (s, 2H), 2.12 (s, 3H), 1.79-1.63 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 139.7, 132.2, 130.7, 130.0, 127.8, 122.4, 53.7, 43.7, 40.9, 36.2, 29.3. 4 4-bromobenzaldehyde N-(4- ESI + MS: calcd for 1 bromobenzyl)- C₁₇H₂₂BrN: 319.09; found: green solid adamantylamine 320.1 (MH⁺) 70% 5 3-fluorobenzaldehyde N-(3- ¹H NMR (CDCl₃, 1 fluorobenzyl)- 400 MHz): δ 7.26 (m, 1H), white solid adamantylamine 7.15 (m, 2H), 6.95 (m, 100% 1H), 4.10 (bs, 1H), 3.85 (s, 2H), 2.12 (s, 3H), 1.79-1.62 (m, 12H). ESI + MS: calcd for C₁₇H₂₂FN: 259.17; found: 260.2 (MH⁺) 6 3-hydroxybenzaldehyde N-(3- ¹H NMR (CDCl₃, 1 hydroxybenzyl)- 400 MHz): δ 7.06 (t, 1H, J = 7.6 Hz), pale adamantylamine 6.83 (s, 1H), yellow solid 6.75 (d, 1H, J = 7.6 Hz), 98% 6.63 (d, 1H, J = 8 Hz), 3.83 (s, 2H), 3.49 (bs, 1H), 2.18 (s, 3H), 1.93-1.67 (m, 12H). ¹³C NMR (DMSO-d6, 100 MHz): δ 156.3, 137.2, 127.7, 117.9, 114.6, 113.2, 52.0, 42.3, 38.8, 34.6, 27.6. ESI + MS: calcd for C₁₇H₂₃NO: 257.18; found: 258.1 (MH⁺) 7 2- N-(2- ESI + MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)- C₁₈H₂₅NO: 271.19; found: pale adamantylamine 272.2 (MH⁺) yellow solid 32% 8 3- N-(3- ESI + MS: calcd for 1 methoxybenzaldehyde methoxybenzyl) C₁₈H₂₅NO: 271.19; found: green oil adamantyl-amine 272.2 (MH⁺) 40% 9 4- N-(4- ¹H NMR (CDCl₃, 1 methoxybenzaldehyde methoxybenzyl)- 400 MHz): δ 7.19 (d, 2H, J = 8.4 Hz), green solid adamantyl-amine 6.77 (d, 2H, J = 8.4 Hz), 42% 3.70 (s, 3H), 3.64 (s, 2H), 2.01 (s, 3H), 1.65-1.54 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 158.5, 129.6, 113.8, 55.2, 51.4, 44.3, 42.4, 36.6, 29.6. ESI + MS: calcd for C₁₈H₂₅NO: 271.19; found: 272.2 (MH⁺) 10 2-nitrobenzaidehyde N-(2- ¹H NMR (CDCl₃, 1 nitrobenzyl)- 400 MHz): δ 7.85 (d, 1H, J = 8.0 Hz), orange solid adamantylamine 6.68 (d, 1H, J = 7.6 Hz), 44% 7.52 (t, 1H, J = 7.2 Hz), 7.34 (t, 1H, J = 7.6 Hz), 3.96 (s, 2H), 2.04 (s, 3H), 1.69-1.56 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 149.3, 133.1, 131.8, 127.7, 124.5, 51.2, 42.7, 42.2, 36.7, 29.6. ESI + MS: calcd for C₁₇H₂₂N₂O₂: 286.17; found: 287.2 (MH⁺) 11 4-nitrobenzaldehyde N-(4- ESI + MS: calcd for 1 nitrobenzyl)- C₁₇H₂₂N₂O₂: 286.17; orange solid adamantylamine found: 287.2 (MH⁺) 58% 12 4-methyl 4- N-(4- ¹H NMR (CDCl₃, 1 formylbenzoate carbethoxybenzyl)- 400 MHz): δ 7.99 (d, 2H, J = 8.4 Hz), white solid adamantylamine 7.46 (d, 2H, J = 8.4 Hz), 100% 6.37 (bd, 1H), 3.90 (s, 5H), 2.12 (s, 3H), 1.81-1.62 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 176.1, 166.4, 139.4, 129.7, 129.3, 55.5, 51.9, 43.1, 39.2, 35.6, 28.9. ESI + MS: calcd for C₁₉H₂₅NO₂: 299.19; found: 300.1 (MH⁺) 13 5-bromo-2- 4-bromo-2-((1- ¹H NMR (CDCl₃, 2 hydroxybenzaldehyde adamantylino)methyl)- 400 MHz): δ 7.28 (dd, 1H, white solid phenol J = 2.4 and 8.8 Hz), 15% 7.14 (dd, 1H, J = 2.4 and 25.6 Hz), 6.73 (dd, 1H, J = 8.4 and 34 Hz), 5.17 (bs, 2H), 3.95 (s, 2H), 2.12 (s, 3H), 1.84-1.61 (m, 12H). ESI + MS: calcd for C₁₇H₂₂BrNO: 335.09; found: 336.2 (MH⁺) 14 2-bromo-5- N-(2-bromo-5- ¹H NMR (CDCl₃, 1 methoxybenzaldehyde methoxybenzyl)adamantyl- 400 MHz): δ 7.46 (d, 1H, J = 2.4 Hz), white solid amine 7.31 (dd, 1H, J = 2.4 55% and 8.8 Hz), 6.71 (d, 1H, J = 8.8 Hz), 3.82 (s, 3H), 3.76 (s, 2H), 3.19 (bs, 1H), 2.10 (s, 3H), 1.74-1.62 (m, 12H). ¹³C NMR (CDCl₃. 100 MHz): δ 156.5, 132.6, 130.7, 111.8, 55.5, 51.8, 42.1, 39.6, 36.6, 29.5, ESI + MS: calcd for C₁₈H₂₄BrNO: 349.10; found: 350.1 (MH⁺) 15 2-methoxy-5- N-[(2-methoxy-5- 1 bromobenzaldehyde bromo)benzyl]- white solid adamantylamine 100% 16 picolinaldehyde N-((pyridin-2- ¹H NMR (CDCl₃, 1 yl)methyl)adamantylamine 400 MHz): δ 8.52 (d, 1H, J = 4.8 Hz), brown solid 7.67 (dt, 1H, J = 1.6 55% and 7.6 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.21 (dd, 1H, J = 4.8 and 6.8 Hz), 4.17 (s, 3H), 3.76 (s, 2H), 2.14 (s, 3H), 1.92-1.64 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 148.7, 137.1, 122.8, 114.0, 54.5, 43.9, 40.4, 36.0, 29.2. ESI + MS: calcd for C₁₅H₂₂N₂: 242.18; found: 243.2 (MH⁺) 17 nicotinaldehyde N-((pyridin-3- ¹H NMR (CDCl₃, 1 yl)methyl)adamantylamine 400 MHz): δ 8.59 (s, 1H), white solid 8.52 (d, 1H, J = 6.6 Hz), 93% 7.92 (d, 1H, J = 8.0 Hz), 7.31 (m, 1H), 4.00 (s, 2H), 2.16 (s, 3H), 1.90-1.63 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 150.1, 149.1, 138.3, 129.6, 123.7, 56.4, 40.9, 39.2, 35.7, 29.1. ESI + MS: calcd for C₁₅H₂₂N₂: 242.18; found: 243.2 (MH⁺) 18 isonicotinaldehyde N-((pyridin-4- ¹H NMR (CDCl₃, 1 yl)methyl)adamantylamine 400 MHz): δ 8.53 (d, 1H, J = 4.4 Hz), pale yellow 7.38 (d, 1H, J = 5.2 Hz), solid 3.91 (s, 2H), 61% 2.13 (s, 3H), 1.80-1.61 (m, 12H). ESI + MS: calcd for C₁₆H₂₂N₂: 242.18; found: 243.2 (MH⁺) 19 5-methylfuran-2- N-((5-methylfuran-2- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 6.22 (d, 1H, J = 2.8 Hz), yellow solid 5.83 (d, 1H, J = 2.0 Hz), 8.4% 5.80 (s, 1H), 3.89 (s, 2H), 2.19 (s, 3H), 2.07 (s, 3H), 1.79 (m, 6H), 1.60 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 152.6, 145.4, 111.3, 106.6, 55.5, 39.0, 36.1, 35.6, 28.9, 13.2. ESI + MS: calcd for C₁₆H₂₃NO: 245.18; found: 246.2 (MH⁺) 20 5-methylthiophene-2- N-((5-methylthiophen-2- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)- 400 MHz): δ 6.80 (d, 1H, J = 3.2 Hz), yellow solid cyclohexanamine 6.57 (d, 1H, J = 3.2 Hz), 89% 5.33 (bs, 1H), 3.98 (s, 2H), 2.43 (s, 3H), 2.11 (s, 3H), 1.78 (m, 6H), 1.66 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 139.7, 138.3, 126.5, 124.9, 53.3, 41.1, 39.0, 36.3, 29.4, 15.3. ESI + MS: calcd for C₁₆H₂₃NS: 261.16; found: 262.2 (MH⁺) 21 Furan-3-carbaldehyde N-[(3- ¹H NMR (CDCl₃, 1 furyl)methyl]- 400 MHz): δ 7.51 (s, 1H), yellow solid adamantylamine 7.36 (s, 1H), 6.52 (s, 1H), 70% 3.84 (s, 2H), 2.15 (s, 3H), 1.89-1.64 (m, 12H). ESI + MS: calcd for C₁₅H₂₁NO: 231.16; found: 232.2 (MH⁺) 22 1-methyl-1H-imidazole- N-((1-methyl-1H-imidazol- ¹H NMR (CDCl₃, 1 5-carbaldehyde 5- 400 MHz): δ 7.53 (s, 1H), white solid yl)methyl)adamantylamine 6.97 (s, 1H), 6.71 (bs, 100% 1H), 3.81 (s, 2H), 3.70 (s, 3H), 2.12 (s, 3H), 1.76-1.62 (m, 12H). 23 1-methyl-1H-imidazole- N-[(5-N- ¹H NMR (CDCl₃, 1 2-carbaldehyde methylimidazolyl)methyl]- 400 MHz): δ 7.75 (bs, 1H), white solid adamantylamine 6.96 (s, 1H), 6.837 (s, 100% 1H), 4.15 (s, 2H), 3.72 (s, 3H), 2.14 (s, 3H), 1.83-1.64 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 131.8, 126.2, 121.8, 54.3, 40.1, 36.1, 29.3. ESI + MS: calcd for C₁₅H₂₃N₃: 245.18; found: 246.2 (MH⁺) 24 Benzo[d][1,3]dioxole-4- Benzo[d][1,3]dioxol-4- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 6.87 (d, 1H, J = 8.4 Hz), white solid 6.79 (t, 1H, J = 7.6 Hz), 100% 6.73 (dd, 1H, J = 1.2 and 7.6 Hz), 5.97 (s, 2H), 3.82 (s, 2H), 3.22 (bs, 1H), 2.11 (s, 3H), 1.78-1.62 (m, 12H). ESI + MS: calcd for C₁₈H₂₃NO₂: 285.17; found: 286.2 (MH⁺) 25 6-nitro[d][1,3]dioxole-5- N-((5- ¹H NMR (CDCl₃, 400 MHz): δ 1 carbaldehyde nitrobenzo[d][1,3]dioxol-6- 7.56 (s, 1H), 7.25 (s, 1H), brown solid yl)methyl)adamantylamine 6.36 (bs, 1H), 6.13 (s, 2H), 54% 4.18 (s, 2H), 2.19 (s, 3H), 1.99-1.67 (m, 12H). ESI + MS: calcd for C₁₈H₂₂N₂O₄: 330.16; found: 331.2 (MH⁺) 26 Quinoline-3- N-((quinolin-3- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 8.91 (s, 1H), yellow solid 8.22 (s, 1H), 8.08 (d, 1H, J = 8.4 Hz), 100% 7.81 (d, 1H, J = 8.4 Hz), 7.68 (t, 1H, J = 7.2 Hz), 7.53 (t, 1H, J = 7.6 Hz), 4.02 (s, 2H), 3.31 (bs, 1H), 2.11 (s, 3H), 1.88-1.62 (m, 12H). ESI + MS: calcd for C₂₀H₂₄N₂: 292.19; found: 293.3 (MH⁺) 27 Quinoline-4- N-((quinolin-4- ESI + MS: calcd for 1 carbaldehyde yl)methyl)adamantylamine C₂₀H₂₄N₂: 292.19; found: orange solid 293.2 (MH⁺) 100% 28 1-methyl-1H-indole-2- N-((1-methyl-1H-indol-2- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)adamantylamine 400 MHz): δ 7.54 (d, 1H, J = 7.6 Hz), yellow solid 7.28 (d, 1H, J = 8.0 Hz), 100% 7.17 (t, 1H, J = 7.2 Hz), 7.06 (t, 1H, J = 7.6 Hz), 6.38 (s, 1H), 3.92 (s, 2H), 3.79 (s, 3H), 2.11 (s, 3H), 1.75-1.63 (m, 12H). ESI + MS: calcd for C₂₀H₂₆N₂: 294.21; found: 295.2 (MH⁺) 29 2-phenylacetaldehyde N- ESI + MS: calcd for 2 phenethyladamantylamine C₁₈H₂₅N₂: 255.20; found: colorless oil 256.3 (MH⁺) 5% 30 3-phenylpropanal N-(3- ¹H NMR (CDCl₃, 1 phenylpropyl)- 400 MHz): δ 8.02 (bs, 1H), white solid adamantylamine 7.26 (m, 2H), 7.16 (m, 100% 3H), 2.78 (t, 2H, J = 7.6 Hz), 2.62 (t, 2H, J = 8.4 Hz), 2.06 (s, 2H), 1.85 (s, 6H), 1.62 (m, 6H), ¹³C NMR (CDCl₃, 100 MHz): δ 128.5, 128.4, 128.3, 126.0, 55.2, 38.9, 38.8, 35.8, 33.2, 28.9, 28.3. ESI + MS: calcd for C₁₉H₂₇N: 269.22; found: 270.3 (MH⁺) 31 2- N-(2- ¹H NMR (CDCl₃, 1 (benzyloxy)- (benzyloxy)ethyl)- 400 MHz): δ 7.33 (m, 5H), orange solid acetaldehyde adamantylamine 4.53 (s, 2H), 3.69 (t, 2H, J = 5.2 Hz), 100% 2.96 (t, 2H, J = 5.2 Hz), 2.12 (s, 3H), 1.78 (m, 5H), 1.66 (m, 7H). ESI + MS: calcd for C₁₉H₂₇NO: 285.21; found: 286.3 (MH⁺) 32 cinnamaldehyde N- ¹H NMR (CDCl₃, 1 cinnamyladamantylamine 400 MHz): δ 8.81 (bs, 1H), yellow solid 7.36-7.11 (m, 5H), 6.59 (d, 100% 1H, J = 16 Hz), 6.35 (dt, 1H, J = 6.8 and 15.6 Hz), 3.54 (d, 2H, J = 6.4 Hz), 2.00 (s, 3H), 1.84-1.55 (m, 12H). ESI + MS: calcd for C₁₉H₂₅N: 267.20; found: 268.3 (MH⁺) 33 paraformaldehyde N-methyl(3- ¹H NMR (CDCl₃, 2 bromobenzyl)- 400 MHz): δ 7.51 (s, 1H), colorless oil adamantylamine 7.34 (d, 1H, J = 7.6 Hz), 23% 7.25 (d, 1H, J = 6.8 Hz), 7.17 (t, 1H, J = 7.6 Hz), 3.53 (s, 2H), 2.13 (s, 6H), 1.77 (s, 6H), 1.66 (m, 6H). ESI + MS: calcd for C₁₈H₂₄BrN: 333.11; found: 334.0 (MH⁺)

TABLE A2 Compounds which are 2-aminoadamantane derivatives, prepared by process A starting from 2- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 34 Benzaldehyde N-benzyl-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 7.55 (m, 2H), white oil 7.37 (m, 3H), 6.33 (bs, 100%  1H), 3.05 (s, 1H), 2.28-1.59 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 131.5, 130.1, 128.9, 60.2, 48.4, 37.1, 36.8, 30.4, 29.2, 26.9, 26.6, 22.8. ESI + MS: calcd for C₁₇H₂₃N: 241.18; found: 242.2 (MH⁺) 35 2-bromobenzaldehyde N-(2-bromobenzyl)-2- LC-MS (ES⁺) m/z 1 adamantylamine 320.1 (M + H)⁺ colorless oil ¹H NMR (CDCl₃, 62% 400 MHz): δ 7.70 (d, 1H, J = 7.6 Hz), 7.56 (d, 1H, J = 7.6 Hz), 7.33 (t, 1H, J = 7.2 Hz), 7.18 (m, 1H), 5.42 (bs, 1H), 4.11 (s, 2H), 3.02 (s, 1H), 2.20-1.59 (m, 14H). ESI + MS: calcd for C₁₇H₂₂BrN: 319.09; found: 320.1 (MH⁺) 36 3-bromobenzaldehyde N-(3-bromobenzyl)-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 7.66 (s, 1H), white solid 7.53 (d, 1H, J = 6.8 Hz), 60% 7.46 (d, 1H, J = 8.4 Hz), 7.26 (m, 1H), 4.02 (s, 2H), 2.98 (s, 1H), 2.22-1.61 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 132.7, 131.8, 128.5, 122.8, 60.8, 48.3, 37.3, 36.9, 30.7, 29.8, 27.1, 26.9. ESI + MS: calcd for C₁₇H₂₂BrN: 319.09; found: 320.1 (MH⁺) 37 4-bromobenzaldehyde N-(4-bromobenzyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 1 adamantylamine 7.50 (d, 1H, J = 8.4 Hz), white solid 7.43 (d, 1H, J = 8.0 Hz), 5.65 (bs, 27% 1H), 4.00 (s, 2H), 2.97 (s, 1H), 2.22-1.60 (m, 14H). ESI + MS: calcd for C₁₇H₂₂BrN: 319.09; found: 320.1 (MH⁺) 38 2-fluorobenzaldehyde N-(2-fluorobenzyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 2 adamantylamine 7.42 (td, 1H, J = 1.2 and 7.2 Hz), yellow solid 7.22 (m, 1H), 7.33 (td, 9.6%  1H, J = 0.8 and 7.2 Hz), 7.03 (t, 1H, J = 9.6 Hz), 3.87 (s, 2H), 2.81 (s, 1H), 2.33 (bs, 1H), 2.04 (d, 2H, J = 12.4 Hz), 1.87 (s, 2H), 1.84 (m, 4H), 1.70 (m, 4H), 1.52 (d, 2H, J = 12 Hz). ESI + MS: calcd for C₁₇H₂₂FN: 259.17; found: 260.2 (MH⁺) 39 3-fluorobenzaldehyde N-(3-fluorobenzyl)-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 7.34 (m, 3H), white solid 7.03 (m, 1H), 4.08 (s, 2H), 100%  3.01 (s, 1H), 2.22-1.61 (m, 14H). ESI + MS: calcd for C₁₇H₂₂FN: 259.17; found: 260.2 (MH⁺) 40 4-fluorobenzaldehyde N-(4-fluorobenzyl)-2- ¹H NMR (CDCl₃, Short pad adamantylamine 400 MHz): δ 7.33 (dd, 2H, yellow solid J = 5.6 and 8.4 Hz), 5.2%  7.00 (t, 2H, J = 8.8 Hz), 3.77 (s, 2H), 2.79 (s, 1H), 2.04 (d, 2H, J = 12.4 Hz), 1.85 (m, 6H), 1.70 (m, 4H), 1.52 (d, 2H, J = 12.4 Hz). ESI + MS: calcd for C₁₇H₂₂FN: 259.17; found: 260.2 (MH⁺) 41 3-hydroxybenzaldehyde N-(3-hydroxybenzyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 1 adamantylamine 7.25 (s, 1H), 7.18 (t, 1H, J = 7.6 Hz), white 6.87 (dd, 1H, J = 2.0 foam and 8.4 Hz), 6.80 (d, 1H, J = 7.2 Hz), 88% 4.04 (s, 2H), 3.12 (s, 2H), 2.24-1.62 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 157.7, 131.7, 129.9, 121.1, 116.9, 116.9, 116.9, 60.6, 48.4, 36.9, 36.7, 30.3, 29.1, 26.7, 26.5. ESI + MS: calcd for C₁₇H₂₃NO: 257.18; found: 258.1 (MH⁺) 42 2- N-(2-methoxybenzyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 1 methoxybenzaldehyde adamantylamine 7.42 (dd, 1H, J = 1.2 and 7.6 Hz), white solid 7.33 (m, 1H), 6.96 (t, 54% 1H, J = 8 Hz), 5.66 (bs, 1H), 4.09 (s, 2H), 3.88 (s, 3H), 3.10 (s, 1H), 2.19-1.63 (m, 14H). ESI + MS: calcd for C₁₈H₂₅NO: 271.19; found: 272.2 (MH⁺) 43 3- N-(3-methoxybenzyl)-2- ¹H NMR (CDCl₃, 1 methoxybenzaldehyde adamantylamine 400 MHz): δ 7.32-6.83 (m, white solid 4H), 3.97 (s, 2H), 3.83 (s, 48% 3H), 2.94 (s, 1H), 2.18-1.58 (m, 14H). ESI + MS: calcd for C₁₈H₂₅NO: 271.19; found: 272.2 (MH⁺) 44 4- N-(4-methoxybenzyl)-2- ¹H NMR (CDCl₃, 1 methoxybenzaldehyde adamantylamine 400 MHz): δ 7.39 (d, 2H, J = 8.8 Hz), white solid 6.89 (d, 2H, J = 8.4 Hz), 45% 5.62 (bs, 1H), 3.96 (s, 2H), 3.79 (s, 3H), 2.97 (s, 1H), 2.15-1.59 (m, 14H). ESI + MS: calcd for C₁₈H₂₅NO: 271.19; found: 272.2 (MH⁺) 45 2-nitrobenzaldehyde N-(2-nitrobenzyl)-2- ESI + MS: calcd for 1 adamantylamine C₁₇H₂₂N₂O₂: 286.17; yellow oil found: 287.2 (MH⁺) 59% 46 4-nitrobenzaldehyde N-(4-nitrobenzyl)-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 8.20 (d, 2H, J = 8.4 Hz), yellow oil 7.63 (d, 2H, J = 8.4 Hz), 56% 3.99 (s, 2H), 2.82 (s, 1H), 2.20-1.54 (m, 14H). ESI + MS: calcd for C₁₇H₂₂N₂O₂: 286.17; found: 287.2 (MH⁺) 47 4-methyl-4- N-(4-carbethoxybenzyl)-2- ¹H NMR (CDCl₃, 1 formylbenzoate adamantylamine 400 MHz): δ 8.86 (bs, 1H), white solid 7.97 (d, 2H, J = 8.4 Hz), 100%  7.57 (d, 2H, J = 8.4 Hz), 4.11 (s, 2H), 3.85 (s, 3H), 3.02 (s, 1H), 2.17-1.54 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 166.3, 136.6, 130.5, 130.0, 129.9, 60.8, 52.1, 48.1, 37.0, 36.7, 30.3, 29.2, 26.7, 26.5. ESI + MS: calcd for C₁₉H₂₅NO₂: 299.19; found: 300.1 (MH⁺) 48 5-bromo-2- 4-bromo-2-((2- ESI + MS: calcd for 2 hydroxybenzaldehyde adamantylamino)methyl)- C₁₇H₂₂BrNO: 335.09; pale yellow phenol found: 336.1 (MH⁺) solid 18% 50 5-bromo-2- N-(5-bromo-2- ESI + MS: calcd for 1 methoxybenzaldehyde methoxybenzyl)-2- C₁₈H₂₄BrNO₂: 349.10; white solid adamantylamine found: 350.1 (MH⁺) 56% 51 5-fluoro-2- N-(5-fluoro-2-nitrobenzyl)- ESI + MS: calcd for 4 nitrobenzaldehyde 2-adamantylamine C₁₇H₂₁FN₂O₂: 304.16; colorless oil found: 305.2 (MH⁺) 2.3%  52 2,5- N-(2,5- ¹H NMR (CDCl₃, 6, 2 difluorobenzaldehyde difluorobenzaldehyde)-2- 400 MHz): δ 7.67-7.62 (m, yellow solid adamantylamine 1H), 7.19-7.15 (m, 1H), 28% 7.11-6.93 (m, 1H), 4.24 (s, 2H), 3.11 (s, 1H), 2.24 (bs, 2H), 1.95-1.89 (m, 6H), 1.75 (m, 4H), 1.67 (m, 2H). ESI + MS: calcd for C₁₇H₂₁F₂N: 277.16; found: 278.2 (MH⁺) 53 picolinaldehyde N-((pyridin-2-yl)methyl)-2- ESI + MS: calcd for 1 adamantylamine C₁₆H₂₂N₂: 242.18; found: yellow oil 243.2 (MH⁺) 71% 54 nicotinaldehyde N-((pyridin-3-yl)methyl)-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 8.62 (s, 1H), yellow solid 8.55 (d, 1H, J = 4.4 Hz), 79% 8.00 (s, 1H), 7.32 (m, 1H), 3.99 (s, 2H), 2.91 (s, 1H), 2.17-1.57 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 150.0, 149.1, 137.8, 130.7, 123.8, 60.9, 46.5, 37.3, 37.0, 30.6, 30.1, 27.1, 26.9, 22.0. ESI + MS: calcd for C₁₆H₂₂N₂: 242.18; found: 243.2 (MH⁺) 55 isonicotinaldehyde N-((pyridin-4-yl)methyl)-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 8.58 (m, 2H), yellow solid 7.44 (d, 1H, J = 4.0 Hz), 46% 7.31 (d, 1H, J = 5.6 Hz), 3.95 (s, 2H), 2.86 (s, 1H), 2.17-1.56 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 150.0, 149.1, 137.8, 130.7, 123.8, 60.9, 46.5, 37.3, 37.0, 30.6, 30.1, 27.1, 26.9, 22.0. ESI + MS: calcd for C₁₆H₂₂N₂: 242.18; found: 243.2 (MH⁺) 56 5-methylfuran-2- N-((5-methylfuran-2- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)-2- 400 MHz): δ 6.33 (d, 1H, J = 2.8 Hz), yellow oil adamantylamine 5.93 (d, 1H, J = 2.0 Hz), 59% 4.80 (bs, 1H), 4.01 (s, 2H), 3.00 (s, 1H), 2.28 (s, 3H), 2.16-1.59 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 152.8, 146.3, 111.7, 106.7, 60.7, 41.4, 37.4, 37.1, 30.7, 29.9, 27.2, 26.9, 13.6. ESI + MS: calcd for C₁₆H₂₃NO: 245.18; found: 246.2 (MH⁺) 57 5-methylthiophene-2- N-((5-methylthiophen-2- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)-2- 400 MHz): δ 6.86 (d, 1H, J = 3.2 Hz), yellow oil adamantylamine 6.62 (d, 1H, J = 2.4 Hz), 55% 5.39 (bs, 1H), 4.10 (s, 2H), 3.00 (s, 1H), 2.46 (s, 3H), 2.14-1.57 (m, 14H). ESI + MS: calcd for C₁₆H₂₃NS: 261.16; found: 262.1 (MH⁺) 58 furan-3-carbaldehyde N-((furan-3-yl)methyl)-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 7.58 (d, 1H, J = 6.8 Hz), orange solid 7.42 (s, 1H), 61% 6.74 (d, 1H, J = 13.6 Hz), 4.01 (s, 2H), 3.07 (s, 1H), 2.28-1.42 (m, 14H). ESI + MS: calcd for C₁₅H₂₁NO: 231.16; found: 232.1 (MH⁺) 59 1-methyl-1H-imidazole- N-((1-methyl-1H-imidazol- ¹H NMR (CDCl₃, 1 5-carbaldehyde 5-yl)methyl)-2- 400 MHz): δ 7.62 (s, 1H), white solid adamantylamine 7.01 (s, 1H), 5.75 (bs, 100%  1H), 3.95 (s, 2H), 3.80 (s, 3H), 2.99 (s, 1H), 2.14-1.58 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 138.9, 129.0, 124.8, 61.2, 37.6, 37.2, 36.9, 32.1, 30.6, 30.0, 29.9, 27.0, 26.8. ESI + MS: calcd for C₁₅H₂₃N₃: 245.19; found: 246.1 (MH⁺) 60 1-methyl-1H-imidazole- N-[(5-N- ¹H NMR (CDCl₃, 1 2-carbaldehyde methylimidazolyl)methyl]- 400 MHz): δ 7.08 (bs, 1H), white solid 2-adamantylamine 7.02 (d, 1H, J = 1.2 Hz), 100%  6.88 (d, 1H, J = 1.2 Hz), 4.12 (s, 2H), 3.80 (s, 3H), 3.14 (s, 1H), 2.13-1.58 (m, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 141.0, 126.2, 122.4, 62.3, 39.7, 37.2, 36.9, 33.6, 30.5, 29.8, 27.0, 26.8. ESI + MS: calcd for C₁₅H₂₃N₃: 245.19; found: 246.2 (MH⁺) 61 Benzo[d][1,3]dioxole-4- Benzo[d][1,3]dioxol-4- ¹H NMR (CDCl₃, 2 carbaldehyde yl)methyl)-2- 400 MHz): δ 6.84 (d, 1H, J = 7.6 Hz), white solid adamantylamine 6.80 (t, 1H, J = 7.6 Hz),  9% 6.74 (dd, 1H, J = 1.2 and 7.6 Hz), 5.96 (s, 2H), 3.79 (s, 2H), 2.78 (s, 1H), 2.11 (s, 1H), 2.05-1.49 (m, 14H). ESI + MS: calcd for C₁₈H₂₃NO₂: 285.17; found: 286.2 (MH⁺) 62 6-nitro[d][1,3]dioxole-5- N-((5- ESI + MS: calcd for 1 carbaldehyde nitrobenzo[d][1,3]dioxol-6- C₁₈H₂₂N₃O₄: 330.16; brown solid yl)methyl)-2- found: 331.2 (MH⁺) 62% adamantylamine 63 Quinoline-3- N-((quinolin-3-yl)methyl)- ¹H NMR (CDCl₃, 2 carbaldehyde 2-adamantylamine 400 MHz): δ 8.87 (d, 1H, J = 4.4 Hz), yellow solid 8.15 (m, 2H), 100%  7.41 (m, 1H), 7.56 (m, 2H), 6.99 (bs, 1H), 4.30 (s, 2H), 2.92 (s, 1H), 2.21-1.54 (m, 14H). ESI + MS: calcd for C₂₀H₂₄N₂: 292.19; found: 293.2 (MH⁺) 64 Quinoline-4- N-((quinolin-4-yl)methyl)- ¹H NMR (CDCl₃, 1 carbaldehyde 2-adamantylamine 400 MHz): δ 8.87 (d, 1H, J = 4.4 Hz), yellow solid 8.15 (m, 2H), 100%  7.41 (m, 1H), 7.56 (m, 2H), 6.99 (bs, 1H), 4.30 (s, 2H), 2.92 (s, 1H), 2.21-1.54 (m, 14H). ESI + MS: calcd for C₂₀H₂₄N₂: 292.19; found: 293.2 (MH⁺) 65 1-methyl-1H-indole-2- N-((1-methyl-1H-indol-2- ¹H NMR (CDCl₃, 1 carbaldehyde yl)methyl)-2- 400 MHz): δ 7.56 (d, 1H, J = 8.0 Hz), yellow solid adamantylamine 7.31 (d, 1H, J = 8 Hz), 100%  7.22 (t, 1H, J = 7.6 Hz), 7.08 (t, 1H, J = 7.6 Hz), 6.59 (bs, 1H), 4.14 (s, 2H), 3.83 (s, 3H), 3.07 (s, 1H), 2.26-1.58 (m, 14H). ESI + MS: calcd for C₂₀H₂₆N₂: 294.21; found: 295.2 (MH⁺) 66 1-(3- N-(1-(3- ¹H NMR (CDCl₃, 4 bromophenyl)ethanone bromophenyl)ethyl)-2- 400 MHz): δ 7.54 (m, 1H), colorless oil adamantylamine 7.41 (m, 2H), 7.26 (m, 18% 2H), 4.88 (q, 1H, J = 6.4 Hz), 2.74 (bs, 1H), 2.08-1.53 (m, 14H), 1.49 (d, 3H, J = 6.4 Hz). ¹³C NMR (CDCl₃, 100 MHz): δ 147.6, 130.1, 130.0, 129.9, 125.4, 122.5, 59.2, 54.7, 32.5, 31.3, 31.1, 30.6, 27.6, 27.4, 24.2. ESI + MS: calcd for C₁₈H₂₄BrN: 333.11; found: 334.2 (MH⁺) 67 benzophenone N-benzhydryl-2- ¹H NMR (CDCl₃, 4 adamantylamine 400 MHz): δ 7.73 (bs, 1H), white solid 7.29 (m, 10H), 4.57 (t, 1H,  3% J = 7.6 Hz), 3.48 (dd, 1H, J = 1.2 and 7.6 Hz), 3.06 (s, 1H), 2.08 (s, 4H), 1.83 (m, 4H), 1.71-1.64 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 140.7, 129.0, 127.9, 127.3, 61.8, 49.5, 48.1, 37.0, 36.9, 30.5, 29.4, 26.9, 26.5. ESI + MS: calcd for C₂₄H₂₉N: 331.23; found: 331.9 (MH⁺) 68 2- N-(2-(benzyloxy)ethyl)-2- ¹H NMR (CDCl₃, 1 (benzyloxy)- adamantylamine 400 MHz): δ 7.34 (m, 5H), white solid acetaldehyde 4.58 (s, 2H), 3.85 (m, 2H), 79% 3.15 (m, 3H), 2.20-1.64 (m, 14H). ESI + MS: calcd for C₁₉H₂₇NO: 285.21; found: 286.3 (MH⁺) 69 3-phenylpropanal N-(phenylpropyl)-2- ¹³C NMR (CDCl₃, 1 adamantylamine 100 MHz): δ 140.8, 128.4, white solid 128.3, 126.0, 62.5, 45.7, 100%  37.3, 37.1, 33.3, 30.5, 29.9, 28.5, 27.2, 26.8. ESI + MS: calcd for C₁₉H₂₇N: 269.22; found: 270.2 (MH⁺) 70 acetophenone N-(1-phenylethyl)-2- ¹H NMR (CDCl₃, 2 adamantylamine 400 MHz): δ 7.57 (d, 2H, J = 11.2 Hz), colorless oil 7.38 (m, 3H), 18% 4.91 (q, 1H, J = 6.4 Hz), 2.87 (s, 1H), 2.14-1.54 (m, 14H), 1.51 (d, 3H, J = 5.1 Hz). ESI + MS: calcd for C₁₈H₂₅N: 255.20; found: 256.3 (MH⁺) 71 1-(pyridin-2-yl)ethanone N-(1-(pyridin-2-yl)ethyl)-2- ¹H NMR (CDCl₃, 1 adamantylamine 400 MHz): δ 8.58 (d, 1H, J = 4.4 Hz), colorless oil 7.73 (m, 1H), 100%  7.48 (m, 1H), 7.26 (m, 1H), 6.51 (bs, 1H), 4.28 (m, 1H), 3.00 (bs, 1H), 2.18-1.51 (m, 14H), 1.62 (d, 3H, J = 6.4 Hz). ESI + MS: calcd for C₁₇H₂₄N: 256.19; found: 257.2 (MH⁺) 72 1-adamantyl methyl N-(2-adamantylmethyl)-1- ¹H NMR (CDCl₃, 4 ketone (adamantyl)ethanamine 400 MHz): δ 3.25 (s, 1H), white solid 2.50 (q, 1H, J = 5.1 Hz), 4.7%  2.36 (s, 1H), 2.06-1.65 (m, 28H), 1.27 (d, 3H, J = 6.8 Hz). ESI + MS: calcd for C₂₂H₃₅N: 313.28; found: 314.2 (MH⁺) 73 paraformaldehyde N-methyl(3-bromobenzyl)- ¹H NMR (CDCl₃, 400 MHz): δ 2 2-adamantylamine 7.50 (s, 1H), 7.35 (d, 1H, J = 8 Hz), white oil 7.27 (d, 1H, J = 9.2 Hz), 35% 7.17 (t, 1H, J = 7.6 Hz), 3.48 (s, 2H), 2.22-2.14 (m, 5H), 1.86 (m, 4H), 1.72 (m, 4H), 1.47 (m, 2H). ¹³C NMR (CDCl₃, 100 MHz): δ 143.6, 131.5, 129.7, 129.5, 127.2, 122.3, 67.6, 57.5, 38.7, 37.8, 37.3, 31.6, 29.9, 27.6, 27.3. ESI + MS: calcd for C₁₈H₂₄BrN: 333.11; found: 334.0 (MH⁺) 191 cinnamaldehyde N-cinnamyl-2- ¹H NMR (CDCl₃, white solid adamantylamine 400 MHz): δ 7.42-7.27 (m, 100%  5H), 6.63 (d, 1H, J = 15.6 Hz), 6.42 (dt, 1H, J = 6.8 and 16 Hz), 3.70 (d, 2H, J = 6.8 Hz), 3.18 (s, 1H), 2.20-1.43 (m, 14H). ESI + MS: calcd for C₁₉H₂₅N: 267.20; found: 268.3 (MH⁺)

Similarly, the derivatives and the alkylamines of general formula (Ib) as described above and which appear in table A3 and in table A4 are prepared by adding, with stirring, a suspension of an amine (1 equiv.) chosen according to the compound to be prepared (see tables A3 and A4) in methanol to 3-bromobenzaldehyde or 3-fluorobenzaldehyde (1 equiv.) for the compounds of table A3, or 3-bromobenzylamine or 3-fluorobenzylamine (1 equiv.) for obtaining the compounds of table A4, in the presence of BH₃CN on resin (0.75 mmol; 1.5 equiv.) and of acetic acid (1.5 mmol; 84 μl; 3 equiv.). The whole is stirred for 2 days at ambient temperature, filtered, washed with methanol, evaporated, and then purified according to methods known to those skilled in the art.

Tables A3 and A4 give the number of the compound, the reactants used, the name of the compound obtained, the characteristics of the compound and also the code of the purification method used, the appearance of the compound obtained and its yield.

TABLE A3 Alkylamine compounds of general formula (I) prepared by process A starting from 3-halobenzaldehydes Purification method/ Compound appearance/ Compound Reactant 1 Reactant 2 Compound name structure yield 74 3- tert-Butylamine N-(3-bromobenzyl)- ¹H NMR (CDCl₃, 1 bromobenzaldehyde 2-methylpropan-2- 400 MHz): δ 7.59 (s, yellow solid amine 1H), 7.40 (d, 1H, J = 8 Hz), 83% 7.36 (d, 1H, J = 7.6 Hz), 7.19 (t, 1H, J = 7.6 Hz), 4.78 (bs, 1H), 3.82 (s, 2H), 1.26 (s, 9H). ESI + MS: calcd for C₁₁H₁₆BrN: 241.05; found: 242.1 (MH⁺) 75 3- 2,4,4- N-(3-bromobenzyl)- ¹H NMR (CDCl₃, 2 bromobenzaldehyde trimethylpentan- 2,4,4- 400 MHz): δ 7.54 (s, yellow solid 2-amine trimethylpentan-2- 1H), 7.39 (d, 1H, J = 8 Hz), 26% amine 7.33 (d, 1H, J = 7.6 Hz), 7.18 (t, 1H, J = 8 Hz), 3.81 (s, 2H), 1.60 (s, 2H), 1.31 (s, 6H), 1.04 (s, 9H). ¹³C NMR (CDCl₃, 100 MHz): δ 140.0, 132.0, 130.6, 130.0, 127.6, 122.4, 57.2, 51.8, 45.3, 31.7, 27.5. ESI + MS: calcd for C₁₅H₂₄BrN: 297.11; found: 298.1 (MH⁺) 76 3- 2-amino-3- 2-(3- ESI + MS: calcd for 2 bromobenzaldehyde hydroxy-2- bromobenzylamino)- C₁₁H₁₄BrNO₃: 287.02; white solid methyl- 3-hydroxy-2- found: 288.1 (MH⁺) 18% propanoic acid methylpropanoic acid 77 3- 2-amino-2- 2-(3- ¹H NMR (CDCl₃, 2 bromobenzaldehyde (hydroxymethyl)- bromobenzylamino)- 400 MHz): δ 7.54 (s, colorless propane-1,3-diol 2- 1H), 7.41 (d, 1H, J = 8 Hz), oil (hydroxymethyl)- 7.30 (d, 1H, J = 8 Hz), 10% propane-1,3-diol 7.21 (t, 1H, J = 7.6 Hz), 3.77 (s, 2H), 3.66 (s, 6H), 1.98 (bs, 4H). ESI + MS: calcd for C₁₁H₁₆BrNO₃: 289.03; found: 290.1 (MH⁺) 78 3- cyclohexyl- N-(3- ¹H NMR (CDCl₃, 1 bromobenzaldehyde amine bromobenzyl)cyclo- 400 MHz): δ 7.52 (s, pale yellow hexanamine 1H), 7.40 (d, 1H, J = 7.6 Hz), solid 7.29 (d, 1H, J = 7.6 Hz), 100%  7.20 (t, 1H, J = 8 Hz), 3.86 (s, 2H), 2.56 (s, 1H), 2.02 (m, 2H), 1.95 (m, 2H), 1.75 (m, 2H), 1.64 (m, 2H), 1.20 (m, 2H). ¹³C NMR (CDCl₃, 100 MHz): δ 138.9, 132.0, 130.8, 130.1, 127.6, 122.6, 55.8, 48.5, 31.3, 25.6, 24.8. ESI + MS: calcd for C₁₃H₁₈BrN: 267.06; found: 268.0 (MH⁺) 79 3- 4- 4-(3- ¹H NMR (CDCl₃, 1 bromobenzaldehyde aminocyclo- bromobenzylamino)- 400 MHz): δ 7.54 (s, white solid hexanol cyclohexanol 1H), 7.43 (d, 1H, J = 7.6 Hz), 100%  7.32 (d, 1H, J = 7.6 Hz), 7.22 (t, 1H, J = 7.6 Hz), 5.28 (bs, 2H), 3.88 (s, 2H), 3.64 (m, 1H), 2.64 (m, 1H), 2.02 (m, 4H), 1.43-1.23 (m, 2H). ¹³C NMR (CDCl₃, 100 MHz): δ 137.6, 132.2, 131.3, 130.2, 127.7, 125.3, 69.6, 54.9, 48.8, 33.4, 28.7. ESI + MS: calcd for C₁₃H₁₈BrNO: 283.06; found: 284.0 (MH⁺) 80 3-fluorobenzaldehyde cyclohexyl- N-(3- ESI + MS: calcd for 1 amine fluorobenzyl)- C₁₃H₁₈FN: 207.14; white solid cyclo-hexylamine found: 208.12 (MH⁺) 100%  81 3-fluorobenzaldehyde 4- 4-(3- ESI + MS: calcd for 1 aminocyclo- fluorobenzylamino)- C₁₃H₁₈FNO: 223.14; white solid hexanol cyclohexanol found: 224.10 (MH⁺) 100% 82 3- (1- (1-(3- ¹H NMR (CDCl₃, 1 bromobenzaldehyde aminocyclo- bromobenzylamino)- 400 MHz): δ 7.55 (s, pale yellow pentyl)methanol cyclopentyl)- 1H), 7.40 (d, 1H, J = 8 Hz), solid methanol 7.31 (d, 1H, J = 7.6 Hz), 100%  7.18 (t, 1H, J = 7.6 Hz), 6.14 (bs, 2H), 3.77 (s, 2H), 3.47 (s, 2H), 1.72 (m, 4H), 1.57 (m, 4H). ESI + MS: calcd for C₁₃H₁₈BrNO: 283.06; found: 284.1 (MH⁺) 83 3- (1- 1-(3- ESI + MS: calcd for 4 bromobenzaldehyde aminocyclo- bromobenzylamino)- C₁₃H₁₆BrNO₂: 297.04; colorless pentyl)methanol cyclopentane- found: 298.1 (MH⁺) oil carboxylic acid 6.6%  84 3- bicyclo[2.2.1]- N-(3-bromobenzyl)- ESI + MS: calcd for 2 bromobenzaldehyde heptan-2- bicyclo[2.2.1]heptan- C₁₄H₁₈BrN: 279.06; yellow oil amine 2-amine found: 280 (MH⁺) 23% 85 3- 2-aminobicyclo- 2-(3- ESI + MS: calcd for 1 bromobenzaldehyde [2.2.1]heptane- bromobenzylamino)- C₁₅H₁₈BrNO₂: 323.05; white solid 2-carboxylic bicyclo[2.2.1]- found: 324.1 (MH⁺)  8% acid heptane-2-carboxylic acid 86 3- noradamantyl- N-(3-bromobenzyl)- ¹H NMR (CDCl₃, 2 bromobenzaldehyde amine noradamantylamine 400 MHz): δ white solid 10.01 (bs, 1H), 7.48 (m, 88% 2H), 7.31 (m, 3H), 3.93 (s, 2H), 2.27 (s, 2H), 2.11 (t, 1H, J = 6.4 Hz), 2.05 (d, 2H, J = 10 Hz), 1.78 (m, 4H), 1.57 (d, 1H, J = 12.8 Hz), 1.46-1.37 (m, 3H). ¹³C NMR (CDCl₃, 100 MHz): δ 132.1, 130.2, 128.7, 128.6, 69.9, 47.6, 45.4, 42.8, 42.0, 37.1, 34.2. ESI + MS: calcd for C₁₆H₂₀BrN: 305.08; found: 306.1 (MH⁺) 87 3- 3-Amino-1- N-(3-bromobenzyl)- ¹H NMR (CDCl₃, 2 bromobenzaldehyde adamantanol 1-hydroxy-2- 400 MHz): δ 7.53 (s, yellow oil adamantylamine 1H), 7.37 (d, 1H, J = 8 Hz), 17% 7.26 (m, 1H), 7.18 (t, 1H, J = 7.6 Hz), 3.75 (s, 2H), 2.56 (s, 1H), 2.29 (s, 2H), 1.77-1.54 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 138.9, 132.0, 130.8, 130.1, 127.6, 122.6, 55.8, 48.5, 31.3, 25.6, 24.8. ESI + MS: calcd for C₁₇H₂₂BrNO: 335.09; found: 336.1 (MH⁺) 88 3- benzo[d][1,3]- N-(3-bromobenzyl)- 2 bromobenzaldehyde dioxol-5-amine N-((benzo[d][1,3]-  5% dioxol-6-yl)methyl)- (3-bromophenyl)- methanamine 89 3- 2-(4- 2-(3- ESI + MS: calcd for 2 bromobenzaldehyde hydroxybenzyl)- bromobenzylamino)- C₁₇H₁₈BrNO₃: 363.05; white solid 2-amino- 2-(4- found: 364.0 (MH⁺)  2% propanoic acid hydroxybenzyl)- propanoic acid 90 3- 2-(3,4- 2-(3,4- ESI + MS: calcd for 4 bromobenzaldehyde dihydroxy- dihydroxybenzyl)-2- C₁₇H₁₈BrNO₄: 379.04; yellow oil benzyl)-2- (3- found: 380.1 (MH⁺) 20% amino- bromobenzylamino)- propanoic acid propanoic acid 91 3- 2-amino-2- 2-(3- ESI + MS: calcd for 2 bromobenzaldehyde phenylbutanoic bromobenzylamino)- C₁₇H₁₈BrNO₂: 347.05; white solid acid 2-phenylbutanoic found: 348.1 (MH⁺)  9% acid 92 3- 2-amino-2,2- 2-(3- ESI + MS: calcd for 2 bromobenzaldehyde diphenylacetic bromobenzylamino)- C₂₁H₁₈BrNO₂: 395.05; white solid acid 2,2-diphenylacetic found: 396.1 (MH⁺) 1.4% acid 93 3- methyl 2- methyl 2-(3- ESI + MS: calcd for 2 bromobenzaldehyde amino-2- bromobenzylamino)- C₁₈H₂₀BrNO₂: 361.07; colorless benzyl- 2-methyl-3- found: 362.1 (MH⁺) oil propanoate phenylpropanoate 15.5%   94 3- methyl 3-(3- 6 bromobenzaldehyde bromobenzylamino)- 8-azabicyclo[3.2.1]octane- 8-carboxylate 95 3- 8-methyl-8- N-(3- ¹H NMR (CDCl₃, 4 bromobenzaldehyde aza- bromobenzyl)-9- 400 MHz): δ 8.57 (bs, colorless bicyclo[3.2.1]- methyl-9- 1H), 7.49 (s, 1H), oil octan-3-one azabicyclo[3.3.1]- 7.39 (d, 1H, J = 7.6 Hz), 25% nonan-3-amine 7.25 (d, 1H, J = 7.6 Hz), 7.20 (t, 1H, J = 7.6 Hz), 3.78 (s, 2H), 3.44 (m, 3H), 2.75 (s, 3H), 2.64 (m, 2H), 2.10 (m, 2H), 1.61-1.44 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 141.1, 131.4, 130.5, 130.1, 127.0, 122.6, 52.0, 50.6, 46.2, 38.3, 31.5, 24.2, 12.8. 96 3- benzo[d][1,3]- N-(3- ESI + MS: calcd for 2 bromobenzaldehyde dioxol-5-amine bromobenzyl)benzo- C₁₅H₁₄BrNO₂: 319.02; colorless [d][1,3]dioxol-5- found: 320.1 (MH⁺) oil amine 39% 97 3- 2-(3,4- 2-(3- 4 bromobenzaldehyde dihydroxybenzyl)- bromobenzylidene- 10% 2-amino- amino)-2-(3,4- propanoic acid dihydroxyphenyl)- propanoic acid

TABLE A4 Alkylamine compounds of general formula (I) prepared by process A starting from 3-halobenzylamines Purification method/ Compound appearance/ Compound Reactant 1 Reactant 2 Compound name structure yield 98 3- benzaldehyde N-benzyl(3- ¹H NMR (CDCl₃, 400 MHz): 1 bromobenzylamine bromophenyl)- δ 7.52 (s, 1H), white solid methanamine 7.46-7.23 (m, 9H), 78% 5.62 (bs, 1H), 3.93 (s, 2H), 3.34 (s, 2H). ESI + MS: calcd for C₁₄H₁₄BrN: 275.03; found: 276.0 (MH⁺) 99 3- 3- bis(3- ESI + MS: calcd for 1 bromobenzylamine bromobenz- bromobenzyl)- C₁₄H₁₃Br₂N: 352.94; white solid aldehyde amine found: 353.8 (MH⁺) 75% 100 3- 3- N-(3- ¹H NMR (CDCl₃, 400 MHz): 1 bromobenzylamine fluorobenz- fluorobenzyl)(3- δ 7.53 (s, 1H), white solid aldehyde bromophenyl)- 7.45 (d, 1H, J = 8 Hz), 86% methanamine 7.33 (m, 3H), 7.13 (dd, 2H, J = 7.6 and 16 Hz), 7.02 (td, 1H, J = 2 and 8 Hz), 3.89 (s, 2H), 3.86 (s, 2H), 3.50 (bs, 1H). ESI + MS: calcd for C₁₄H₁₃BrFN: 293.02; found: 293.9 (MH⁺) 101 3- 1-methyl-1H- N-(3- ESI + MS: calcd for 1 bromobenzylamine indole-2- bromobenzyl)(1- C₁₇H₁₇BrN₂: 328.06; yellow solid carbaldehyde methyl-1H-indol-2- found: 328.9 (MH⁺) 27% yl)methanamine 102 3- acetophenone N-(3-bromobenzyl)- ¹H NMR (CDCl₃, 400 MHz): 1 bromobenzylamine 1- δ 7.47-7.18 (m, white solid phenylethanamine 9H), 3.94 (q, 1H, J = 6.4 Hz), 34% 3.75 (d, 1H, J = 13.2 Hz), 3.61 (d, 1H, J = 13.6 Hz), 1.55 (d, 3H, J = 6.4 Hz). 103 3- 1-(3- N-(3-bromobenzyl)- ¹H NMR (CDCl₃, 400 MHz): 1 bromobenzylamine bromophenyl)- 1-(3- δ 7.54-7.19 (m, white solid ethanone bromophenyl)- 8H), 3.87 (q, 1H, J = 6.8 Hz), 43% ethanamine 3.73 (d, 1H, J = 13.6 Hz), 3.60 (d, 1H, J = 13.6 Hz), 1.50 (d, 3H, J = 6.8 Hz). ESI + MS: calcd for C₁₅H₁₅Br₂N: 366.96; found: 367.8 (MH⁺) 104 3- 1-(pyridin-2- N-(3-bromobenzyl)- ¹H NMR (CDCl₃, 400 MHz): 1 bromobenzylamine yl)ethanone 1-(pyridin-2- δ 8.63 (d, 1H, J = 4.4 Hz), colorless yl)ethanamine 7.75 (t, 2H, oil J = 2 and 8 Hz), 100%  7.47-7.18 (m, 5H), 4.21 (q, 1H, J = 6.8 Hz), 3.86 (d, 1H, J = 13.2 Hz), 3.76 (d, 1H, J = 13.2 Hz), 1.58 (d, 3H, J = 6.8 Hz). ESI + MS: calcd for C₁₄H₁₅BrN₂: 290.04; found: 291.0 (MH⁺) 105 3- quinuclidin-3- N-(3- ¹³C NMR (CDCl₃, 1 bromobenzylamine amine bromobenzyl)- 100 MHz): δ 141.5, colorless quinuclidin-3-amine 131.0, 130.4, 130.1, oil 126.7, 122.6, 63.8, 63% 55.7, 53.4, 51.6, 50.6, 46.4, 46.2, 45.5, 45.3, 26.5, 24.2, 22.2, 17.4, 16.6. ESI + MS: calcd for C₁₄H₁₉BrN₂: 294.07; found: 295.0 (MH⁺) 106 3- 9-Methyl-9- (1R*,5S*)-N-(3- ¹H NMR (CDCl₃, 1 bromobenzylamine azabicyclo[3.3.1]- bromobenzyl)bicyclo- 400 MHz): δ 7.66 (s, white solid nonan-3-one [3.3.1]nonan-9- 1H), 7.55 (d, 1H, J = 8 Hz), 100%  amine 7.47 (d, 1H, J = 8 Hz), 7.26 (m, 1H,), 4.02 (s, 2H), 2.80 (s, 1H), 2.08 (m, 2H), 1.88-1.47 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 134.3, 133.0, 132.0, 130.4, 128.7, 122.7, 59.1, 47.7, 31.9, 29.2, 24.0, 21.3, 20.4. ESI + MS: calcd for C₁₆H₂₂BrN: 307.09; found: 308.0 (MH⁺) 107 3- 8-methyl-8-aza- N-(3-bromobenzyl)- ¹³C NMR (CDCl₃, 1 bromobenzylamine bicyclo[3.2.1]- 8-methyl-8-aza- 100 MHz): δ 142.1, colorless octan-3-amine bicyclo[3.2.1]octan- 130.9, 130.2, 130.1, oil 3-amine 126.6, 122.6, 62.0, 100%  51.8, 49.0, 47.9, 46.3, 43.2, 24.9. ESI + MS: calcd for C₁₅H₂₁BrN₂: 308.09; found: 309.0 (MH⁺) 108 3- 1-adamantyl N-(1-(3- ¹³C NMR (CDCl₃, 1 bromobenzylamine methyl ketone bromophenyl)ethyl)- 100 MHz): δ 137.4, white solid adamantylamine 132.3, 131.4, 130.4, 84% 127.9, 122.7, 60.9, 49.4, 38.0, 37.7, 37.2, 36.7, 35.5, 28.3, 28.1. ESI + MS: calcd for C₁₉H₂₆BrN: 347.12; found: 348.0 (MH⁺) 109 3- noradamantyl- N-(3-fluorobenzyl)- ESI + MS: calcd for 1 fluorobenzylamine amine noradamantylamine C₁₆H₂₀FN: 245.16; 100%  found: 246.09 (MH⁺)

The compounds of table A5 are prepared according to process A, adding a microwave heating step.

TABLE A5 Purification method/ appearance/ Compound Compound name Compound characteristics yield 138 N-(3-chlorobenzyl)adamantylamine ¹H NMR (CDCl₃, 400 MHz): δ 7.38 (s, 1H), 1 7.26 (m, 3H), 6.86 (bs, 1H), 3.82 (s, 2H), white solid 2.13 (s, 3H), 1.79-1.63 (m, 12H).  88% ¹³C NMR (CDCl₃, 100 MHz): δ 139.2, 134.2, 129.7, 129.3, 127.8, 127.4, 53.9, 43.6, 40.7, 40.6, 36.2, 29.3. ESI + MS: calcd for C₁₇H₂₂ClN: 275.14; found: 276.1 (MH⁺) 139 N-(3-chlorobenzyl)-2-adamantylamine ¹H NMR (CDCl₃, 400 MHz): δ 7.47 (s, 1H), 1 7.41-7.28 (m, 3H), 3.99 (s, 2H), 2.97 (s, white solid 1H), 2.13 (m, 4H), 1.87 (m, 4H),  88% 1.73-1.59 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 135.3, 134.6, 130.1, 129.8, 128.8, 127.9, 60.8, 48.3, 37.3, 37.0, 30.6, 29.8, 27.1, 26.8. ESI + MS: calcd for C₁₇H₂₂ClN: 275.14; found: 276.2 (MH⁺) 140 N-(3-iodobenzyl)-2-adamantylamine ¹H NMR (CDCl₃, 400 MHz): δ 7.80 (s, 1H), 1 7.65 (d, 1H, J = 8 Hz), 7.49 (d, 1H, J = 7.2 Hz), white solid 7.11 (t, 1H, J = 7.6 Hz), 3.93 (s, 2H), 100% 2.94 (s, 1H), 2.15 (m, 4H), 1.89 (m, 4H), 1.73-1.59 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 138.6, 137.7, 135.7, 130.5, 129.0, 94.4, 60.9, 48.2, 37.3, 37.0, 30.6, 29.8, 27.1, 26.8. ESI + MS: calcd for C₁₇H₂₂IN: 367.08; found: 367.6 (MH⁺) 141 N-(2,2-diphenylethyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 7.73 (bs, 1 adamantylamine 1H), 7.29 (m, 10H), 4.57 (t, 1H, J = 7.6 Hz), white solid 3.48 (dd, 1H, J = 1.2 and 7.6 Hz), 100% 3.06 (s, 1H), 2.08 (s, 4H), 1.83 (m, 4H), 1.71-1.64 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 140.7, 129.0, 127.9, 127.3, 61.8, 49.5, 48.1, 37.0, 36.9, 30.5, 29.4, 26.9, 26.5. ESI + MS: calcd for C₂₄H₂₉N: 331.23; found: 331.9 (MH⁺) 142 N-(naphthalen-1-ylmethyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 8.14 (d, 1H, 1 adamantylamine J = 8.4 Hz), 7.88 (d, 1H, J = 8 Hz), white solid 7.84 (d, 1H, J = 8.4 Hz), 7.76 (bs, 1H), 7.68 (d, 100% 1H, J = 7.2 Hz), 7.59 (t, 1H, J = 7.2 Hz), 7.49 (m, 2H), 4.51 (s, 2H), 3.13 (s, 1H), 2.14 (m, 4H), 1.86 (m, 4H), 1.72-1.60 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 133.7, 131.7, 129.5, 129.2, 128.9, 128.8, 126.9, 126.0, 125.4, 122.9, 61.6, 46.1, 37.2, 37.0, 30.6, 30.1, 27.0, 26.8. ESI + MS: calcd for C₂₁H₂₅N: 291.2; found: 291.8 (MH⁺) 143 N-(phenanthren-9-ylmethyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 8.74 (m, 1H), 1 adamantylamine 8.65 (d, 1H, J = 8 Hz), 8.20 (bs, 1H), white solid 7.91 (m, 2H), 7.70-7.57 (m, 4H), 4.48 (s, 2H), 100% 3.14 (s, 1H), 2.14 (m, 2H), 2.05 (m, 2H), 1.87 (m, 4H), 1.74-1.60 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 131.0, 130.7, 130.5, 130.2, 129.8, 128.9, 127.9, 127.3, 127.2, 127.0, 126.9, 126.8, 123.7, 123.4, 122.4, 61.9, 46.8, 37.3, 37.1, 30.7, 30.2, 30.2, 27.1, 26.9. ESI + MS: calcd for C₂₅H₂₇N: 341.21; found: 341.8 (MH⁺) 144 4-((adamantylamino)methyl)benzoic ¹H NMR (CDCl₃, 400 MHz): δ 7.83 (d, 2H, 1 acid J = 8.4 Hz), 7.49 (d, 2H, J = 8 Hz), white solid 4.16 (s, 2H), 3.27 (s, 1H), 2.32-1.67 (m, 14H). 100% ¹³C NMR (CDCl₃, 100 MHz): δ 170.4, 134.5, 133.5, 130.2, 129.8, 61.2, 48.2, 36.9, 36.7, 30.1, 29.0, 26.7, 26.5. ESI + MS: calcd for C₁₈H₂₃NO₂: 285.17; found: 286.1 (MH⁺)

Process B: Formation of Acid Salts

A solution of HCl in Et₂O (2N) is added to a solution of the amine (corresponding to the desired hydrochloride salt) in CH₂Cl₂. The salt is obtained after filtration and drying of the precipitate under vacuum.

TABLE B1 Salts derived from 1- or 2-aminoadamantane Purification method/ appearance/ Compound Compound name Compound characteristics yield 110 N-(3- ¹H NMR (CDCl₃, 400 MHz): δ 9.55 (bs, 1H), 1 bromobenzyl)adamantylamine 7.81 (s, 1H), 7.66 (d, 1H, J = 7.6 Hz), 7.39 (d, 1H, J = 8 Hz), white solid hydrochloride salt 7.23 (t, 1H, J = 8 Hz), 3.86 (t, 2H, J = 6 Hz), 2.12 (s, 3H), 1.95 (s, 5H), 1.65 (s, 4H), 1.55 (s, 3H). 111 N-(5-bromo-2- ¹H NMR (CDCl₃, 400 MHz): δ 8.94 (bs, 1H), 1 methoxybenzyl)adamantylamine 7.66 (d, 1H, J = 2.4 Hz), 7.38 (dd, 1H, J = 2.4 and 8.8 Hz), white solid hydrochloride salt 6.75 (d, 1H, J = 8.4 Hz), 3.91 (s, 5H), 2.13 (s, 3H), 1.89, 1.67 and 1.53 (3s, 12H). ¹³C NMR (DMSO-d⁶, 100 MHz): δ 155.7, 133.2, 131.8, 121.2, 111.2, 110.5, 56.1, 54.4, 36.6, 36.0, 34.1, 27.5. 112 N-(2-bromobenzyl)-2- ¹H NMR (CDCl₃, 400 MHz): δ 9.84 (bs, 1H), 1 adamantylamine hydrochloride 7.78 (s, 1H), 7.51 (dd, 1H, J = 2.4 and 10.8 Hz), white solid salt 7.30 (m, 2H), 4.18 (s, 2H), 3.05 (s, 1H), 2.48-1.55 (s, 14H). ¹³C NMR (CDCl₃, 100 MHz): δ 1133.3, 132.5, 132.4, 130.7, 129.1, 122.8, 60.2, 47.4, 37.1, 36.7, 30.4, 29.0, 26.8, 26.6.

Process C

The 1-aminoadamantane, 2-aminoadamantane or noradamantylamine derivatives of general formula (Ic) as described above and which appear, respectively, in tables C1, C2 and C3 are prepared as follows: a stirred suspension of 1-aminoadamantane, 2-aminoadamantane or noradamantylamine (1 equiv.) in methanol is added to an aldehyde (1 equiv.) chosen according to the compound to be prepared (see tables C1, C2 and C3). The whole is mixed for two days at ambient temperature and then evaporated.

TABLE C1 Compounds which are 1-aminoadamantane derivatives, prepared by process C starting from 1- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 113 3- (E)-N-(3- ¹H NMR (DMSO, white solid bromobenzaldehyde bromobenzylidene)- 400 MHz): δ 8.30 (s, adamantylamine 1H), 7.94 (s, 1H), 7.74 (d, 1H, J = 7.6 Hz), 7.62 (d, 1H, J = 7.6 Hz), 7.40 (t, 1H, J = 7.6 Hz), 2.12 (s, 3H), 1.74-1.64 (m, 12H). 114 3-fluorobenzaldehyde (E)-N-(3- ¹H NMR (DMSO, yellow solid fluorobenzylidene)- 400 MHz): δ 8.32 (s, 90% adamantylamine 1H), 7.59 (d, 1H, J = 8 Hz), 7.55-7.45 (m, 2H), 7.27 (m, 1H), 2.12 (s, 3H), 1.75-1.64 (m, 12H). 115 1-methyl-1H-indole-2- (E)-N-((1-methyl-1H-indol-2- ¹H NMR (DMSO, brown solid carbaldehyde yl)methylene)adamantylamine 400 MHz): δ 8.41 (s, 55% 1H), 7.58 (d, 1H, J = 7.6 Hz), 7.46 (dd, 1H, J = 2.4 and 8.4 Hz), 7.23 (t, 1H, J = 7.6 Hz), 7.05 (t, 1H, J = 7.6 Hz), 6.86 (s, 1H), 4.09 (s, 3H), 2.12 (s, 3H), 1.77-1.64 (m, 12H). ¹³C NMR (CDCl₃, 100 MHz): δ 147.8, 139.8, 136.4, 127.0, 126.9, 123.3, 121.3, 119.7, 109.6, 108.2, 57.8, 43.1, 36.6, 29.6. ESI + MS: calcd for C₂₀H₂₄N₂: 292.19; found: 293.2 (MH⁺) 116 benzaldehyde (E)-N- ¹H NMR (DMSO, brown solid benzylideneadamantylamine 400 MHz): δ 8.31 (s, 99% 1H), 7.75 (m, 2H), 7.42 (m, 3H), 2.12 (s, 3H), 1.75-1.64 (m, 12H).

TABLE C2 Compounds which are 2-aminoadamantane derivatives, prepared by process C starting from 2- adamantylamine Purification method/ Compound appearance/ Compound Aldehyde Compound name characteristics yield 117 3- (E)-N-(3- ¹H NMR (CDCl₃, white solid bromobenzaldehyde bromobenzylidene)- 400 MHz): δ 8.52 (bs, 60% adamantylamine 1H), 7.62 (s, 1H), 7.46 (d, 1H, J = 8 Hz), 7.38 (d, 1H, J = 8 Hz), 7.23 (d, 1H, J = 7.6 Hz), 3.52 (s, 1H), 2.23 (s, 5H), 1.96-1.66 (m, 9H). 118 3-fluorobenzaldehyde (E)-N-(3- ¹H NMR (CDCl₃, white solid fluorobenzylidene)- 400 MHz): δ 8.52 (bs, 74% adamantylamine 1H), 7.34 (m, 1H), 7.23 (d, 1H, J = 7.6 Hz), 7.18 (d, 1H, J = 9.6 Hz), 7.02 (dt, 1H, J = 2 and 8 Hz), 3.51 (s, 1H), 2.23 (s, 3H), 1.96-1.66 (m, 11H).

TABLE C3 Compounds prepared by process C starting from noradamantylamine Compound Compound Reactant 2 Compound name characteristics Yield 119 3- (E)-N-(3- 98% bromobenzaldehyde bromobenzylidene)- noradamantylamine 120 1-methyl-1H-indole-2- (E)-N-((1-methyl-1H-indol-2- 100% carbaldehyde yl)methylene)- noradamantylamine

Process E: Benzoylation

The N-1-adamantylbenzamide and N-2-adamantylbenzamide compounds are prepared as follows: 1-adamantylamine or 2-adamantylamine (1 equiv.) and benzoyl chloride (1.2 equiv.) are added, at 0° C., to a suspension of NaH (1.1 equiv.) in DMF. The mixture is stirred for 24 hours at ambient temperature, evaporated, and then washed with cyclohexane.

TABLE D1 Compounds which are 1-aminoadamantane derivatives prepared by process E starting from 1- adamantylamine Purification method/ Compound Compound appearance/ number Reactant 2 Compound name characteristics yield 121 benzoyl chloride N-1-adamantylbenzamide ¹H NMR (CDCl₃, 400 MHz): δ 6 7.72 (dd, 2H, J = 1.2 and 7.2 Hz), white solid 7.46 (m, 3H), 5.79 (bs,  74% 1H), 2.13 (s, 9H), 1.73 (m, 6H). ¹³C NMR (CDCl₃, 100 MHz): δ 166.6, 136.0, 131.0, 128.4, 126.7, 52.3, 41.7, 36.4, 29.5. 122 benzoyl chloride N-2-adamantylbenzamide ¹H NMR (CDCl₃, 400 MHz): δ 6 7.78 (dd, 2H, J = 1.6 and 6.8 Hz), white solid 7.49 (m, 3H), 6.42 (bs, 100% 1H), 4.27 (m, 1H), 2.06-1.55 (m, 14H). ESI + MS: calcd for C₁₇H₂₁NO: 255.16; found: 256.2 (MH⁺)

The sulfonylation is carried out according to the following process:

Et₃N (138 μl; 1 mmol; 5 equiv.) and benzenesulfonyl chloride (76 al; 0.6 mmol; 3 equiv.) are added to a solution of 1-adamantylamine hydrochloride or 2-adamantylamine hydrochloride (0.2 mmol; 1 equiv.) in CH₂Cl₂ (1 ml). The mixture is stirred at ambient temperature for 24 h, and hydrolyzed with NH₄Cl. The organic phase is washed three times with water, dried over MgSO₄, filtered and evaporated to give the expected product.

Preparation of N-1-adamantylsulfonamide (compound 124)

Starting from 1-adamantylamine, the product obtained is a brown solid (86%).

¹H NMR (CDCl₃, 400 MHz): δ 7.91 (dd, 2H, J=1.6 and 7.2 Hz), 7.53 (m, 3H), 2.01 (s, 3H), 1.79 (m, 6H), 1.58 (m, 6H).

¹³C NMR (CDCl₃, 100 MHz): δ 143.9, 132.0, 128.8, 126.8, 55.2, 43.0, 35.0, 29.4.

Preparation of N-2-adamantylsulfonamide (compound 128)

Starting from 2-adamantylamine, the product obtained is a yellow solid (86%).

¹H NMR (CDCl₃, 400 MHz): δ 7.89 (dd, 2H, J=1.9 and 7.2 Hz), 7.55 (m, 3H), 3.43 (s, 1H), 1.79-1.53 (m, 14H).

¹³C NMR (CDCl₃, 100 MHz): δ 141.2, 132.3, 129.0, 126.8, 57.9, 37.3, 37.1, 32.7, 31.1, 26.8, 26.7.

Nucleophilic Addition

Phenylisocyanate or phenylthioisocyanate (0.75 mmol; 1.5 equiv.) is added, at 0° C., to a stirred suspension of 1-adamantylamine (0.5 mmol; 1 equiv.) in THF (3 ml). The mixture is stirred for 24 hours at ambient temperature and then evaporated;

or phenylisocyanate or phenylthioisocyanate (0.75 mmol; 1.5 equiv.) and triethylamine (1.05 equiv.) are added, at 0° C., to a stirred suspension of 2-adamantylamine hydrochloride (0.5 mmol; 1 equiv.) in DMF (3 ml). The mixture is stirred for 24 hours at ambient temperature, then evaporated, placed in solution in Et₂O, and filtered, and then the filtrate is evaporated.

This process makes it possible to prepare the following compounds:

Preparation of 1-adamantan-1-yl-3-phenylurea (compound 129)

Starting from 1-adamantylamine and phenylisocyanate, a white solid is obtained (95%).

¹H NMR (CDCl₃, 400 MHz): δ 7.35 (m, 3H), 7.11 (m, 2H), 2.18 (s, 3H), 2.00 (s, 6H), 1.68 (s, 6H).

¹³C NMR (CDCl₃, 100 MHz): δ 160.5, 1387, 129.2, 123.7, 121.0, 51.5, 42.2, 36.3, 29.5.

ESI+MS: calcd for C₁₇H₂₂N₂O: 270.17; found: 271.1 (MH⁺).

Preparation of 1-adamantan-2-yl-3-phenylurea (compound 132)

Phenylisocyanate or phenylthioisocyanate (0.75 mmol; 1.5 equiv.) and triethylamine (1.05 equiv.) are added, at 0° C., to a stirred suspension of 2-adamantylamine hydrochloride (0.5 mmol; 1 equiv.) in DMF (3 ml). The mixture is stirred for 24 h at ambient temperature, evaporated, placed in solution in Et₂O and filtered, and then the filtrate is evaporated.

A white solid is obtained (69%).

¹H NMR (CDCl₃, 400 MHz): δ 7.34 (m, 4H), 7.11 (t, 1H, J=6.8 Hz), 3.96 (s, 1H), 1.96 (s, 2H), 1.84-1.61 (m, 12H).

ESI+MS: calcd for C₁₇H₂₂N₂O: 270.17; found: 271.1 (MH⁺).

The process which follows makes it possible to prepare the compounds below: phenyl chloroformate (0.6 mmol; 1.2 equiv.) and triethylamine (2.5 mmol; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 1-adamantylamine hydrochloride or 2-adamantylamine hydrochloride (0.5 mmol; 1 equiv.) in CH₂Cl₂ (4 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH₄Cl, dried over Na₂SO₄, filtered, evaporated and short-pad-purified.

Preparation of adamantan-1-ylcarbamic acid phenyl ester (compound 123)

Starting from 1-adamantylamine and phenyl chloroformate, a white solid is obtained (13%).

¹H NMR (CDCl₃, 400 MHz): δ 7.35 (t, 2H, J=8 Hz), 7.18 (t, 1H, J=7.2 Hz), 7.12 (d, 2H, J=7.6 Hz), 4.88 (bs, 1H), 2.11 (s, 3H), 2.01 (s, 6H), 1.69 (s, 6H).

¹³C NMR (CDCl₃, 100 MHz): δ 150.9, 129.1, 125.0, 121.7, 51.2, 41.7, 36.3, 29.4.

ESI+MS: calcd for C₁₇H₂₁NO₂: 271.16; found: 272.1 (MH⁺).

Preparation of adamantan-2-ylcarbamic acid phenyl ester (compound 126)

Starting from 2-adamantylamine hydrochloride and phenyl chloroformate, a white solid is obtained (17%).

¹H NMR (CDCl₃, 400 MHz): δ 7.36 (t, 2H, J=7.6 Hz), 7.20 (t, 1H, J=7.6 Hz), 7.14 (d, J=8 Hz), 5.36 (bs, 1H), 3.88 (s, 1H), 2.03 (s, 2H), 1.87-1.67 (m, 12H).

¹³C NMR (CDCl₃, 100 MHz): δ 129.2, 125.1, 121.5, 114.9, 55.1, 37.4, 37.0, 32.0, 31.7, 27.1, 27.0.

ESI+MS: calcd for C₁₇H₂₁NO₂: 271.16; found: 272.1 (MH⁺).

Preparation of N-adamantan-1-yl-N-(3-bromobenzyl)benzamide (compound 125)

Benzoyl chloride (0.47 mmol; 55 μl; 3 equiv.) and triethylamine (109 μl; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 1-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in CH₂Cl₂ (3 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH₄Cl, dried over Na₂SO₄, filtered, evaporated and short-pad-purified.

Starting from acetyl chloride, a colorless oil is obtained (26%).

¹H NMR (CDCl₃, 400 MHz): δ 7.39 (dd, 1H, J=1.2 and 10.8 Hz), 7.25 (t, 1H, J=7.6 Hz), 7.17 (d, 1H, J=7.6 Hz), 4.58 (s, 2H), 2.20 (s, 6H), 2.07 (s, 6H), 1.63 (m, 6H).

¹³C NMR (CDCl₃, 100 MHz): δ 172.2, 142.2, 130.3, 130.1, 128.7, 124.2, 123.0, 59.3, 48.0, 39.9, 36.3, 30.1, 25.7.

ESI+MS: calcd for C₁₉H₂₄BrNO: 361.10; found: 362.0 (MH⁺).

Preparation of 1-adamantan-1-yl-1-(3-bromobenzyl)-3-phenylurea (compound 131)

Phenylisocyanate (19 μl; 1.1 equiv.) is added, at 0° C., to a stirred suspension of 1-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in THF (3 ml). The mixture is stirred for 24 h at ambient temperature, evaporated and short-pad-purified.

Starting from phenylisocyanate, a colorless oil is obtained (51%).

¹H NMR (CDCl₃, 400 MHz): δ 7.52-6.98 (m, 9H), 6.13 (bs, 1H), 4.64 (s, 2H), 2.25 (s, 6H), 2.11 (s, 3H), 1.68 (m, 6H).

¹³C NMR (CDCl₃, 100 MHz): δ 155.5, 141.1, 138.9, 130.8, 130.6, 128.9, 128.7 124.2, 123.4, 122.9, 120.0, 58.2, 47.2, 40.4, 36.3, 30.1.

ESI+MS: calcd for C₂₄H₂₇ BrN₂O: 438.13; found: 439.0 (MH⁺).

Preparation of N-adamantan-2-yl-N-(3-bromobenzyl)benzamide (compound 127)

Benzoyl chloride (0.47 mmol; 55 μl; 3 equiv.) and triethylamine (109 μl; 5 equiv.) are added, at ambient temperature, to a stirred suspension of 2-adamantylamine (0.156 mmol; 50 mg; 1 equiv.) in CH₂Cl₂ (2 ml). The mixture is stirred for 24 h at ambient temperature, washed with water, placed in a saturated solution of NH₄Cl, dried over Na₂SO₄, filtered, evaporated and short-pad-purified.

Starting from benzoyl chloride, a white oil is obtained (17%).

¹H NMR (CDCl₃, 400 MHz): δ 7.43 (m, 2H), 7.35 (m, 4H), 7.19 (s, 1H), 7.16 (t, 1H, J=8 Hz), 7.05 (d, 1H, J=7.6 Hz), 4.78 (s, 2H), 4.17 (s, 1H), 2.32 (s, 2H), 2.02-1.66 (m, 12H).

¹³C NMR (CDCl₃, 100 MHz): δ 175.4, 142.1, 137.8, 130.2, 130.0, 129.7, 128.8, 128.4, 127.1, 124.2, 122.8, 60.2, 49.5, 38.0, 37.4, 32.8, 30.0, 27.3, 26.9.

ESI+MS: calcd for C₂₄H₂₆BrNO: 423.12; found: 424.8 (MH⁺).

Synthesis by Click Chemistry

Et₃N (0.83 mmol: 1.1 equiv.), phenylacetylene (0.83 mmol; 1.1 equiv.) or ethynylpyridine (0.83 mmol; 1.1 equiv.), and the 1-adamantylamine-derived azide (0.75 mmol; 1 equiv.) are added to a suspension of Cu/C (50 mg) in 1,4-dioxane (1.5 ml). The mixture is stirred at 60° C. for 2 days, filtered through a short pad, washed with EtOAc and then evaporated. This process makes it possible to prepare the following compounds:

Preparation of 1-adamantan-1-yl-4-phenyl-1H[1,2,3]triazole (compound 145)

Starting from 1-azidoadamantane and phenylacetylene, a brown oil is obtained (96%).

¹H NMR (CDCl₃, 400 MHz): δ 7.84 (dd, 3H, J=1.2 and 8.4 Hz), 7.42 (t, 2H, J=8 Hz), 7.32 (t, 1H, J=7.2 Hz), 2.30 (s, 9H), 1.82 (s, 6H), 1.43 (m, 4H).

¹³C NMR (CDCl₃, 100 MHz): δ 146.5, 140.0, 128.6, 127.6, 125.4, 116.0, 59.4, 42.8, 35.7, 29.3.

ESI+MS: calcd for C₁₈H₂₁N₃: 279.17; found: 280.2 (MH⁺).

Preparation of 1-adamantan-1-ylmethyl-4-phenyl-1H[1,2,3]triazole (compound 146)

Starting from 1-azidomethyladamantane and phenylacetylene, a brown oil is obtained (68%).

¹H NMR (CDCl₃, 400 MHz): δ 7.86 (dd, 2H, J=1.2 and 8.4 Hz), 7.68 (s, 1H), 7.44 (t, 2H, J=7.2 Hz), 7.34 (t, 1H, J=7.6 Hz), 4.08 (s, 2H), 2.02 (s, 3H), 1.58 (m, 12H).

¹³C NMR (CDCl₃, 100 MHz): δ 147.0, 130.7, 128.7, 127.9, 125.6, 120.9, 62.2, 40.2, 36.4, 34.1, 28.0.

ESI+MS: calcd for C₁₉H₂₃N₃: 293.19; found: 294.2 (MH⁺).

Preparation of 2-(1-adamantan-1-yl-1H[1,2,3]triazol-4-yl)pyridine (compound 147)

Starting from 1-azidoadamantane and 2-ethynylpyridine, a brown oil is obtained (39%).

¹H NMR (CDCl₃, 400 MHz): δ 8.58 (d, 1H, J=4.4 Hz), 8.22 (m, 2H), 7.79 (t, 1H, J=7.6 Hz), 7.23 (t, 1H, J=6 Hz), 2.30 (s, 8H), 1.81 (m, 7H).

¹³C NMR (CDCl₃, 100 MHz): δ 150.7, 149.2, 147.3, 136.9, 122.6, 120.1, 118.6, 59.8, 42.9, 35.9, 29.4.

ESI+MS: calcd for C₁₇H₂₀N₄: 280.17; found: 281.2 (MH⁺).

Imidazolines and Oxazoline

Potassium carbonate (415 mg; 3 mmol; 3 equiv.) and iodine (635 mg; 2.5 mmol; 2.5 equiv.) are added to a solution of 1-adamantanemethanol (166 mg; 1 mmol) in tert-butanol (8 ml). The mixture is stirred at 70° C. for 16 h and the amine (1.5 equiv.) diluted in tert-butanol is added. The mixture is refluxed at 70° C. for 2 h, diluted with a saturated solution of Na₂SO₃ (5 ml), and extracted with chloroform (20 ml). The organic phases are washed with 2N NaOH (20 ml) and brine (20 ml), dried over Na₂SO₄, filtered and evaporated.

Preparation of 2-adamantan-1-yl-4,5-dihydro-1H-imidazole (compound 134)

Starting from 1-adamantanemethanol and ethylenediamine, a colorless oil is obtained (66%).

¹H NMR (CDCl₃, 400 MHz): δ 3.59 (s, 4H), 2.04 (s, 3H), 1.89 (s, 6H), 1.73 (m, 6H).

Preparation of 2-adamantan-1-yl-4,5-dihydrooxazole (compound 135)

Starting from 1-adamantanemethanol and 2-aminoethanol, a colorless oil is obtained (2.4%).

¹H NMR (CDCl₃, 400 MHz): δ 4.23 (t, 2H, J=9.6 Hz), 3.83 (t, 2H, J=9.6 Hz), 2.02 (s, 3H), 1.91 (s, 6H), 1.73 (m, 6H).

Preparation of 2-adamantan-1-yl-1-phenyl-4,5-dihydro-1H-imidazole (compound 136)

Starting from 1-adamantanemethanol and N-phenylethylenediamine, a yellow oil is obtained (15%).

¹H NMR (CDCl₃, 400 MHz): δ 7.40-7.18 (m, 5H), 3.82 (t, 2H, J=9.1 Hz), 3.68 (t, 2H, J=9.6 Hz), 1.85 (s, 3H), 1.81 (s, 6H), 1.54 (m, 6H).

¹³C NMR (CDCl₃, 7100 MHz): δ 172.0, 145.0, 129.2, 127.1, 58.2, 52.1, 40.5, 37.5, 36.4, 28.2.

ESI+MS: calcd for C₁₉H₂₄N₂: 280.19; found: 281.2 (MH⁺).

Preparation of 2-adamantan-1-yl-4,5-dicyclohexyl-4,5-dihydro-1H-imidazole (compound 137)

Starting from 1-adamantanemethanol and (1R,2R)-1,2-cyclohexanediamine, a yellow oil is obtained (10%).

¹H NMR (CDCl₃, 400 MHz): δ 4.67 (bs, 1H), 2.84 (bs, 2H), 2.03 (s, 3H), 1.87 (s, 6H), 1.72 (m, 6H).

ESI+MS: calcd for C₁₇H₂₆N₂: 258.21; found: 259.2 (MH⁺).

The synthesis of the amine compounds requires the prior preparation of the following synthesis intermediate:

2-amino-N-phenylbenzamide

2-nitro-N-phenylbenzamide (1 eq., 5 mmol, expected m=1.06 g) is dissolved in 12 ml of methanol. A few drops of acetic acid are added to the reaction medium. Decaborane (0.3 eq., 1.5 mmol, 183 mg) is then added, with palladium on carbon (100 mg, 10% of the mass of the 2-nitro-N-phenylbenzamide). After 3 hours at reflux, the mixture is filtered and then purified by silica chromatography (cyclohexane/ethyl acetate in 70:30 proportions), which gives the compound 2-amino-N-phenylbenzamide with a yield of 88% (933 mg).

¹H NMR (400 MHz, DMSO d⁶)

δ: 9.95 (s, 1H, NH), 7.70-7.68 (d, J=7.6 Hz, 2H, H_(Ar)2′), 7.62-7.59 (d, J=8 Hz, 1H, H_(Ar) 3), 7.33-7.29 (t, J=7.6 Hz, 2H, H_(Ar) 3′), 7.20-7.16 (t, J=8.4 Hz, 1H, H_(Ar) 4), 7.08-7.04 (t, J=7.2 Hz, 1H, H_(Ar) 4′), 6.75-6.73 (d, J=8.4 Hz, 1H, H_(Ar) 6), 6.60-6.56 (t, J=8 Hz, 1H, H_(Ar) 5), 6.29 (2H, NH₂).

MS (ES) m/z 213 (M+H⁺), 120.

Preparation of 2-(3-bromobenzylideneamino)-N-phenylbenzamide (compound 149)

The 2-amino-N-phenylbenzamide (1 eq., 42 mg, 0.2 mmol) is dissolved in 2 ml of methanol with 3-bromobenzaldehyde (1 eq., 23 μl, 0.2 mmol). After an overnight period, the reaction mixture is evaporated (disappearance of the 2-amino-N-phenylbenzamide is observed by NMR) and the imine 149 is formed quantitatively.

¹H NMR (400 MHz, DMSO d⁶) δ : 8.40 (s, 1H, CH), 7.70-6.60 (m, 13H, H_(Ar)).

Preparation of 2-(3-fluorobenzylideneamino)-N-phenylbenzamide (compound 151)

The 2-amino-N-phenylbenzamide (1 eq., 21 mg, 0.1 mmol) is dissolved in 1 ml of methanol with 3-fluorobenzaldehyde (1 eq., 10 al, 0.1 mmol). After an overnight period, the reaction mixture is evaporated (disappearance of the 2-amino-N-phenylbenzamide is observed by NMR) and the imine 151 is formed quantitatively.

¹H NMR (400 MHz, DMSO d⁶) δ : 9.43 (s, 1H, CH), 7.62-6.72 (m, 13H, H_(Ar)).

Amination

DCC (10.9 g; 52.7 mmol; 1.1 equiv.), DMAP (1.17 g, 9.6 mmol, 0.2 equiv.) and aniline (6.1 ml; 67.1 mmol; 1.4 equiv.) are added, at ambient temperature, to a solution of nitro acid (8 g; 47.9 mmol; 1 equiv.) in CH₂Cl₂ (100 ml). The mixture is stirred for 4 days and evaporated. The solid is then solubilized in acetone and then filtered.

The brown filtrate is evaporated, to give a brown solid which is washed with Et₂O to give 2-nitro-N-phenylbenzamide in the form of an orange solid (11.6 g; 71%).

Furthermore, palladium on carbon (550 mg) and decaborane (757 mg, 6.2 mmol; 0.3 equiv.) are added, at ambient temperature, to a solution of 2-nitro-N-phenylbenzamide (5 g; 20.7 mmol; 1 equiv.) in MeOH (65 ml). The mixture is heated at 60° C. for 6 h, filtered through celite, washed with EtOAc and evaporated to give 2-amino-N-phenylbenzamide (brown solid, 4.2 g; 96%), which is used without purification.

An aldehyde (0.2 mmol; 1 equiv.) is added to a solution of 2-amino-N-phenylbenzamide (42 mg; 0.2 mmol; 1 equiv.) in MeOH (2 ml), and the mixture is stirred for 2 days at ambient temperature, evaporated, and purified by a suitable method if necessary.

This process makes it possible to prepare the following compounds:

Preparation of (E)-2-((furan-2-yl)methyleneamino)-N-phenylbenzamide (compound 152)

Starting from furan-2-carbaldehyde, a yellow solid is obtained (99%).

¹H NMR (CDCl₃, 400 MHz): δ 8.02 (dd, 1H, J=1.2 and 8 Hz), 7.40-7.24 (m, 7H), 6.91 (t, 1H, J=8 Hz), 6.70 (d, 1H, J=8 Hz), 6.33 (d, 1H, J=3.2 Hz), 6.25 (dd, 1H, J=2 and 3.2 Hz), 6.06 (d, 1H, J=2 Hz), 4.94 (bs, 1H).

¹³C NMR (CDCl₃, 100 MHz): δ 162.6, 152.2, 145.1, 142.6, 140.6, 133.7, 128.9, 128.8, 126.7, 126.1, 119.7, 117.1, 115.1, 110.3, 109.0, 68.4.

ESI+MS: calcd for C₁₈H₁₄N₂O₂: 290.11; found: 291.1 (MH⁺).

Preparation of (E)-2-((5-methylfuran-2-yl)methyleneamino)-N-phenylbenzamide (compound 154)

Starting from 5-methylfuran-2-carbaldehyde, a yellow solid is obtained (100%).

ESI+MS: calcd for C₁₉H₁₆N₂O₂: 304.12; found: 305.0 (MH⁺).

Preparation of (E)-2-((furan-3-yl)methyleneamino)-N-phenylbenzamide (compound 153)

Starting from furan-3-carbaldehyde, a yellow solid is obtained (97%).

¹H NMR (CDCl₃, 400 MHz): δ 8.02 (d, 1H, J=7.6 Hz), 7.39-7.23 (m, 7H), 6.93 (t, 1H, J=7.6 Hz), 6.70 (d, 1H, J=8 Hz), 6.28 (s, 1H), 6.04 (s, 1H), 4.70 (bs, 1H).

¹³C NMR (CDCl₃, 100 MHz): δ 162.7, 145.5, 143.6, 140.8, 140.4, 133.8, 129.0, 128.9, 126.9, 126.7, 125.5, 119.7, 117.1, 115.2, 108.7, 67.7.

ESI+MS: calcd for C₁₈H₁₄N₂O₂: 290.11; found: 291.1 (MH⁺).

Preparation of (E)-2-(2-fluorobenzylideneamino)-N-phenylbenzamide (compound 157)

Starting from 2-fluorobenzaldehyde, a yellow solid is obtained (53%).

ESI+MS: calcd for C₂₀H₁₅FN₂O: 318.12; found: 319.1 (MH⁺).

Preparation of (E)-2-(3-bromobenzylideneamino)-N-phenylbenzamide (compound 151)

Starting from 3-fluorobenzaldehyde, a yield of 100% is obtained.

ESI+MS: calcd for C₂₀H₁₅FN₂O: 318.12; found: 319.1 (MH⁺).

Preparation of (E)-2-(3-fluorobenzylideneamino)-N-phenylbenzamide (compound 149)

Starting from 3-bromobenzaldehyde, a yield of 100% is obtained.

¹H NMR (DMSO-d⁶, 400 MHz): δ 8.40 (s, 1H), 7.70-6.60 (m, 13H, H).

Preparation of (E)-2-(4-fluorobenzylideneamino)-N-phenylbenzamide (compound 156)

Starting from 4-fluorobenzaldehyde, a yellow oil is obtained (8%).

Purification mode: Short pad

¹H NMR (DMSO d⁶, 400 MHz): δ 9.43 (s, 1H), 7.62-6.72 (m, 13H)

ESI+MS: calcd for C₂₀H₁₅BrN₂O: 318.12; found: 319.2 (MH⁺).

Preparation of (E)-2-(5-fluoro-2-nitrobenzylideneamino)-N-phenylbenzamide (compound 155)

Starting from 5-fluoro-2-nitrobenzaldehyde, a yellow oil is obtained (2.9%).

Purification mode: Short pad

ESI+MS: calcd for C₂₀H₁₄FN₃O₃: 363.34; found: 364.1 (MH⁺).

Preparation of (E)-2-(5-bromo-2-hydroxybenzylideneamino)-N-phenylbenzamide (compound 159)

Starting from 5-bromo-2-hydroxybenzaldehyde, a yellow oil is obtained (92%).

ESI+MS: calcd for C₂₀H₁₅BrN₂O₂: 394.03; found: 395.0 (MH⁺).

Preparation of (E)-2-((1-methyl-1H-indol-2-yl)methyleneamino)-N-phenylbenzamide (compound 158)

Starting from 1-methyl-1H-indole-2-carbaldehyde, a yellow oil is obtained (12%).

Purification mode: Short pad

ESI+MS: calcd for C₂₃H₁₉N₃O: 353.15; found: 354.2 (MH⁺).

Reductive Amination

Preparation of 2-(3-bromobenzylamino)-N-phenylbenzamide (compound 150)

Starting from (E)-2-(3-fluorobenzylideneamino)-N-phenylbenzamide.

Yield=100%.

Preparation of 2-(2-fluorobenzylamino)-N-phenylbenzamide (compound 160)

Starting from (E)-2-(2-fluorobenzylideneamino)-N-phenylbenzamide, a colorless oil is obtained (1%).

Purification mode: Short pad

ESI+MS: calcd for C₂₀H₁₇FN₂O: 320.13; found: 321.0 (MH⁺).

Benzodiazepines

The synthesis of the compounds of general formula (II) requires the prior preparation of the following synthesis intermediates:

tert-butyl N-[(phenylcarbamoyl)methyl]carbamate

N-boc-glycine (1 eq., 5.71 mmol, 1.0 g) is dissolved in 10 ml of dichloromethane at 0° C. DCC (1.1 eq., 6.28 mmol, 1.3 g) is then added in small portions. Finally, aniline (1.4 eq., 8.0 mmol, 0.73 ml) is added at ambient temperature. After two days at ambient temperature, the content of the round-bottom flask is filtered and then evaporated. Silica gel column purification (mixture of ethyl acetate/N-hexane in a gradient of 50:50 to 80:20) makes it possible to obtain 740 mg of purified tert-butyl N-[(phenylcarbamoyl)-methyl]carbamate (51%).

¹H NMR (400 MHz, CDCl₃)

δ: 9.89 (s, 1H, NH), 7.57-7.55 (d, J=7.6 Hz, 2H, H_(Ar)), 7.30-7.26 (1, J=7.6 Hz, 2H, H_(Ar)), 7.02-7.00 (d, J=7.2 Hz, 1H, H_(Ar)), 5.19 (s, 1H, NH), 3.70-3.69 (d, J=6 Hz, 2H, CH₂), 1.38 (s, 9H, (CH₃)₃).

MS (ES) m/z 251 (M+H⁺), 195, 151, 94.

tert-butyl(4-methoxyphenylcarbamoyl)methylcarbamate

N-boc-glycine (1 eq., 7.2 mmol, 1.26 g) is dissolved in 10 ml of dichloromethane at 0° C. DCC (1.1 eq., 8.0 mmol, 1.65 g) is then added in small portions. Finally, para-anisidine (1.4 eq., 10 mmol, 1.23 g) is added at ambient temperature. After two days at ambient temperature, the content of the round-bottom flask is filtered and then evaporated. Silica gel column purification (98:2 mixture of acetone/dichloromethane) makes it possible to obtain 1.154 g of purified tert-butyl (4-methoxyphenylcarbamoyl)methylcarbamate compound (57%).

¹H NMR (400 MHz, CDCl₃)

δ: 9.74 (s, 1H, NH), 7.48-7.45 (d, J=9.2 Hz, 2H, H_(Ar)), 7.00 (s, 1H, NH), 6.87-6.84 (d, J=8.8 Hz, 2H, H_(Ar)), 3.70 (s, 3H, OCH₃), 3.67-3.66 (d, J=6 Hz, 2H, CH₂), 1.38 (s, 9H, (CH₃)₃).

MS (ES) m/z 281 (M+H⁺), 225, 181, 124.

2-amino-N-phenylacetamide

The tert-butyl N-[(phenylcarbamoyl)methyl]carbamate compound (1 eq., 3 mmol, 450 mg) is dissolved in a 2:1 mixture of dichloromethane/trifluoroacetic acid. After one hour, the 2-amino-N-phenylacetamide product is quantitatively obtained after evaporation and used directly in Pictet-Spengler reaction tests.

MS (ES) m/z 151 (M+H⁺), 94.

2-amino-N-(4-methoxyphenyl)acetamide

The tert-butyl(4-methoxyphenylcarbamoyl)methylcarbamate compound (1 eq., 3 mmol, 540 mg) is dissolved in a 2:1 mixture of dichloromethane/trifluoroacetic acid. After one hour, 2-amino-N-(4-methoxyphenyl)acetamide is quantitatively obtained after evaporation and used directly in Pictet-Spengler reaction tests.

MS (ES) m/z 181 (M+H⁺), 124.

2-benzoyl-4-bromoaniline

Pathway 1: 4-bromoaniline (1 eq., 0.05 mol, 8.6 g) is dissolved in benzoyl chloride (2.7 eq., 0.135 mol, 15.7 ml). The reaction mixture is heated to 180° C. and then zinc chloride (1.25 eq., 0.063 mol, 8.5 g) is added. After heating for two hours at 205° C., the mixture is cooled to 120° C. and then 60 ml of 3N hydrochloric acid are added. After refluxing and separation of the hot acid layer by settling out, the water-insoluble residue is dissolved in 80 ml of 70% sulfuric acid, brought to reflux for 8 hours, and then poured into a large amount of ice-cold water. After the addition of ethyl acetate (3×50 ml), the organic phases are combined and then evaporated. After purification by HPLC, the yield is less than 1% (the mass obtained was approximately 200 mg).

Pathway 2: 2-aminobenzophenone (1 eq., 5 mmol, 0.986 g) is dissolved in dichloromethane at 0° C. N-bromosuccinimide (1 eq., 5 mmol, 0.890 g) is then added in small portions. The temperature of the reaction mixture is allowed to return to ambient temperature over approximately two hours. The reaction mixture is then evaporated and 2-benzoyl-4-bromoaniline is quantitatively obtained.

¹H NMR (400 MHz, CDCl₃)

δ: 7.64-7.63 (d, J=7.2 Hz, 2H, 2′), 7.56 (s, 1H, 6), 7.55-7.54 (d, J=2.4 Hz, 1H, 4′), 7.50-7.47 (t, J=7.6 Hz, 2H, 3′), 7.38-7.35 (q, J=8.8-2.4 Hz, 1H, 4), 6.66-6.64 (d, J=8.4 Hz, 1H, 3), 6.09 (s, 2H, NH₂).

MS (ES) m/z 276 (M+H⁺), 198, 105.

Preparation of 4,5-dihydro-7-methoxy-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one (compound 167)

2-amino-N-(4-methoxyphenyl)acetamide (1 eq., 0.5 mmol, 140 mg) is dissolved in 2 ml of acetonitrile. Benzaldehyde (1.5 eq., 0.75 mmol, 76 μl) is added to the reaction medium, followed by 1 ml of trifluoroacetic acid. After refluxing for 3 hours, the mixture is evaporated and then purified by silica gel chromatography (mixture of cyclohexane/ethyl acetate in a gradient of 80:20 to 50:50), which makes it possible to obtain 16 mg of compound 167, i.e. a yield of 12%.

¹H NMR (400 MHz, CDCl₃)

δ: 7.50-6.60 (m, 8H, H_(Ar)), 6.44 (s, 1H, NH), 5.30 (s, 1H, CH), 3.82-3.72 (dd, J=10 et 15.6 Hz, 2H, CH₂), 3.73 (s, 3H, OCH₃), 3.49 (s, 1H, NH).

MS (ES) m/z 269 (M+H⁺), 222, 204, 145, 106.

Preparation of 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (compound 162)

In a round-bottomed flask fitted with a Dean-Stark apparatus and a condenser, aminobenzophenone (2.85 eq., 5 mmol, 1.0 g) is dissolved in 15 ml of pyridine containing 4 Å molecular sieve. Ethyl glycinate hydrochloride (1 eq., 1.75 mmol, 244 mg) is then added, and the mixture is then brought to reflux for 3 hours. Approximately 5 ml of pyridine are withdrawn from the Dean-Stark apparatus and replaced with 5 ml of fresh pyridine. After an overnight period at 110° C., the pyridine is evaporated off, while adding 10 ml of toluene, and the residue is then dissolved in 30 ml of dichloromethane and 30 ml of 2.5% Na₂CO₃. The combined organic phases are washed with a saturated solution of sodium chloride and then dried with anhydrous Na₂SO₄ and, finally, evaporated to give the crude product. Purification on a silica gel column (mixture of dichloromethane/acetone in a concentration gradient of from 95:5 to 80:20) makes it possible to obtain 217 mg of purified product 161, i.e. a yield of 52.5%.

¹H NMR (400 MHz, CDCl₃)

δ: 8.45 (s, 1H, NH), 7.64-7.26 (m, 9H, H_(Ar)), 4.34 (s, 2H, CH₂).

MS (ES) m/z 237 (M+H⁴).

Preparation of 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (compound 170)

In a round-bottomed flask fitted with a Dean-Stark apparatus and a condenser, 4-chloro-2-aminobenzophenone (2.85 eq., 5 mmol, 1.16 g) is dissolved in 15 ml of pyridine containing 4 Å molecular sieve. Methyl glycinate hydrochloride (1 eq., 1.75 mmol, 220 mg) is then added, and the mixture is then brought to reflux for 3 hours. After an overnight period at 110° C., the pyridine is evaporated off, while adding 10 ml of toluene, and the residue is then dissolved in 30 ml of dichloromethane and 30 ml of 2.5% Na₂CO₃. The combined organic phases are washed with a saturated solution of sodium chloride, then dried with anhydrous Na₂SO₄ and, finally, evaporated to give the crude product. Purification on a silica gel column (mixture of cyclohexane/ethyl acetate in a gradient of from 90:10 to 50:50) makes it possible to obtain 80 mg of product 170 (17%).

¹H NMR (400 MHz, CDCl₃)

δ: 9.42 (s, 1H, NH), 7.78-7.16 (m, 8H, H_(Ar)), 4.33 (s, 2H, CH₂).

MS (ES) m/z 271 (M+H⁺).

Preparation of 7-bromo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (compound 163)

In a round-bottomed flask fitted with a Dean-Stark apparatus and a condenser, 2-benzoyl-4-bromoaniline (2 eq., 0.47 mmol, 130 mg) is dissolved in 5 ml of pyridine. Methyl glycinate hydrochloride (1 eq., 1.24 mmol, 30 mg) is then added and the mixture is then brought to reflux for 3 hours. Approximately 2 ml of pyridine are withdrawn from the Dean-Stark apparatus and replaced with 2 ml of fresh pyridine. After an overnight period at 110° C., the pyridine is evaporated off, while adding 5 ml of toluene, and the residue is then dissolved in 20 ml of dichloromethane and 20 ml of 2.5% Na₂CO₂. The combined organic phases are washed with a saturated solution of sodium chloride, then dried over anhydrous Na₂SO₄ and, finally, evaporated to give the crude product. Purification on a silica gel column (mixture of cyclohexane/ethyl acetate in a concentration gradient of from 90:10 to 50:50) makes it possible to obtain 100 mg of product 163, i.e. 26%.

¹H NMR (400 MHz, CDCl₃)

δ: 9.26 (s, 1H, NH), 7.90-7.32 (m, 8H, H_(Ar)), 4.37 (s, 2H, CH₂).

MS (ES) m/z 315 (MH⁺).

Preparation of 5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (compound 169)

Compound 162 (1 eq., 0.42 mmol, 100 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 1.27 mmol, loading: 4.4 mmol/g, 290 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 3 days. After filtration and then evaporation, the product obtained is purified by silica gel chromatography (cyclohexane/ethyl acetate in a gradient of from 80:20 to 1:2), and the desired product 169 is obtained with a yield of 60%.

¹H NMR (400 MHz, CDCl₃)

δ: 9.12 (s, 1H, NH), 7.35-6.67 (m, 9H, H_(Ar)), 5.21 (s, 1H, CH), 3.35-3.25 (q, J=10-14.8 Hz, 2H, CH₂), 3.21 (s, 1H, NH).

MS (ES) m/z 239 (M+H⁺), 182, 132, 91.

Preparation of 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (compound 171)

Compound 170 (1 eq., 0.22 mmol, 60 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 0.66 mmol, loading: 4.4 mmol/g, 150 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 5 days. After filtration and then evaporation, the product obtained is purified by silica gel chromatography (cyclohexane/ethyl acetate in a gradient of from 80:20 to 1:2), and the desired product 171 is obtained with a yield of 55%.

¹H NMR (400 MHz, CDCl₃)

δ: 9.15 (s, 1H, NH), 7.40-6.86 (m, 8H, H_(Ar)), 5.20 (s, 1H, CH), 3.45-3.36 (q, J=10-13.6 Hz, 2H, CH₂), 3.10 (s, 1H, NH).

MS (ES) m/z 273 (M+H⁺), 221, 91.

Preparation of 7-bromo-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one (compound 164)

Compound 163 (1 eq., 0.25 mmol, 80 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 0.75 mmol, loading: 4.4 mmol/g, 170 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 3 days. After filtration and then evaporation, the product obtained is purified by silica gel chromatography (cyclohexane/ethyl acetate in a gradient of from 80:20 to 1:2), and the desired product 164 is obtained with a yield of 52%.

¹H NMR (400 MHz, CDCl₃)

δ: 8.48 (s, 1H, NH), 7.52-6.86 (m, 8H, H_(Ar)), 5.18 (s, 1H, CH), 3.45-3.35 (q, J=10-14.8 Hz, 2H, CH₂), 2.86 (s, 1H, NH).

MS (ES) m/z 317 (M+H⁺), 91.

Preparation of 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one (compound 165)

1,2-Diaminobenzene (1 eq., 2 mmol, 216 mg) and ethyl 3-oxo-3-phenylpropanoate (1 eq., 2 mmol, 384 mg) are mixed together in a pill bottle flask. The reaction mixture is then heated at 150° C. for 2 hours. The residue is then diluted in ethyl acetate and hydrochloric acid (pH˜5), and then the organic phase is washed with water and then with a saturated solution of sodium chloride. Finally, the solution is dried with Na₂SO₄ and then evaporated. Purification on a silica gel column (70:30 cyclohexane/ethyl acetate) makes it possible to obtain 325 mg of 165, i.e. a yield of 69%.

¹H NMR (400 MHz, CDCl₃)

δ: 12.88 (s, 1H, NH), 8.17-6.64 (m, 9H, H_(Ar)), 5.50 (s, 2H, CH₂).

MS (ES) m/z 237 (M+H⁺), 195.

Preparation of 4-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (compound 166)

Compound 165 (1 eq., 0.42 mmol, 100 mg) is dissolved in 2 ml of methanol. The reducing agent on polymer beads (3 eq., 1.27 mmol, loading: 4.4 mmol/g, 290 mg) is added, as are a few drops of acetic acid (50 μl). The reaction takes place at ambient temperature for 3 days. After filtration then evaporation, the product obtained is purified by silica gel chromatography (cyclohexane/ethyl acetate in a gradient of from 80:20 to 1:2), and the desired product 166 is obtained with a yield of 77%.

The second process that follows also allows the synthesis of compound 166: 1,2-diaminobenzene (1 eq., 10 mmol, 1.08 g) is mixed with cinnamic acid (1 eq., 10 mmol, 1.48 g) in a pill bottle flask. The reaction mixture is then heated at 150° C. without solvent for two hours. The residue is diluted in dichloromethane and a 5% Na₂CO₃ solution. The organic phase is extracted several times with the Na₂CO₃ solution, and then with a saturated solution of sodium chloride. Finally, the solution is dried with Na₂SO₄ and then evaporated. Purification on a silica gel column (cyclohexane/ethyl acetate in a gradient of from 80:20 to 1:1) makes it possible to isolate 166 with a yield of 12% (286 mg).

¹H NMR (400 MHz, CDCl₃)

δ: 9.15 (s, 1H, NH), 7.40-6.72 (m, 9H, H_(Ar)), 5.76 (s, 1H, NH), 4.91-4.89 (m, 1H, CH), 2.54-2.52 (d, J=6 Hz, 2H, CH₂).

MS (ES) m/z 239 (M+H⁺), 197, 131.

Preparation of ethyl 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxylate (compound 168)

Compound 166 (1 eq., 0.218 mmol, 52 mg) is dissolved with ethyl chloroformate (1.2 eq., 0.262 mmol, 25 μl) in a solution composed of dichloromethane and triethylamine in 10:1 proportions. After two hours at ambient temperature, the content of the pill bottle flask is evaporated. Purification on a silica gel column (cyclohexane/ethyl acetate in a gradient of from 90:10 to 1:1) makes it possible to isolate 15 mg of 168, i.e. a yield of 21%.

¹H NMR (400 MHz, CDCl₃)

δ: 9.10 (s, 1H, NH), 7.62-6.72 (m, 9H, H_(Ar)), 5.10 (s, 1H, CH), 4.24 (m, 2H, CH₂), 2.62-2.61 (d, J=6 Hz, 2H, CH₂), 1.46 (t, J=8 Hz, 3H, CH₃).

MS (ES) m/z 311 (M+H⁺), 269, 207, 135.

Synthesis of benzo[b][1,4]diazepines

A β-keto ester (0.5 mmol; 1 equiv.) is added to a stirred suspension of diamine (0.5 mmol; 54 mg; 1 equiv.) in toluene (2 ml). The mixture is stirred at reflux (120° C.) for 3 h. The mixture is diluted in EtOAc, acidified (ph 5), extracted with EtOAc, filtered, evaporated and washed with Et₂O to give the desired compound.

Starting from benzene-1,2-diamine Preparation of (E)-4-m-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 176)

Starting from ethyl 3-oxo-3-m-tolylpropanoate, a brown solid is obtained (31%).

¹H NMR (CDCl₃, 400 MHz): δ 7.94 (s, 1H), 7.91 (d, 1H, J=8 Hz), 7.69 (bs, 1H), 7.54 (d, 1H, J=8.8 Hz), 7.38 (t, 1H, J=7.6 Hz), 7.31 (m, 2H), 7.05 (dd, 1H, J=1.6 and 7.6 Hz), 3.59 (s, 2H), 2.45 (s, 3H).

ESI+MS: calcd for C₁₆H₁₄N₂O: 250.11; found: 250.1 (MH⁺).

Preparation of (E)-4-(3-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 177)

Starting from ethyl 3-(3-methoxyphenyl)-3-oxopropanoate, a brown solid is obtained (20%).

¹H NMR (CDCl₃, 400 MHz): δ 7.68 (m, 3H), 7.55 (dd, 1H, J=2 and 8 Hz), 7.40 (t, 1H, J=8.4 Hz), 7.28 (m, 1H), 7.06 (dt, 2H, J=2.8 and 8 Hz), 3.91 (s, 3H), 3.58 (s, 2H).

¹³C NMR (CDCl₃, 100 MHz): δ 167.3, 159.9, 158.8, 139.8, 138.9, 129.7, 128.9, 128.3, 126.5, 125.2, 121.6, 120.4, 117.7, 112.2, 55.5, 39.9.

ESI+MS: calcd for C₁₆H₁₄N₂O₂: 266.11; found: 267.0 (MH⁺).

Preparation of (E)-4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 178)

Starting from ethyl 3-(3-nitrophenyl)-3-oxopropanoate, a brown solid is obtained (23%).

¹H NMR (CDCl₃, 400 MHz): δ 9.00 (t, 1H, J=2 Hz), 8.40 (d, 1H, J=8 Hz), 8.35 (dd, 1H, J=1.6 and 8 Hz), 7.73 (bs, 1H), 7.68 (t, 1H, J=8.4 Hz), 7.55 (m, 1H), 7.32 (m, 2H), 7.09 (m, 1H), 3.62 (s, 2H).

ESI+MS: calcd for C₁₅H₁₁N₃O₃: 281.08; found: 282.0 (MH⁺).

Preparation of (E)-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 179)

Starting from ethyl 3-(3-chlorophenyl)-3-oxopropanoate, a brown solid is obtained (15%).

¹H NMR (CDCl₃, 400 MHz): δ 8.14 (t, 1H, J=1.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.76 (bs, 1H), 7.53-7.41 (m, 3H), 7.29 (m, 2H), 7.07 (dd, 1H, J=1.2 and 6.8 Hz), 3.56 (s, 2H).

¹³C NMR (CDCl₃, 100 MHz): δ 167.1, 157.3, 139.7, 139.3, 135.0, 131.0, 129.9, 128.9, 128.4, 127.8, 126.9, 125.8, 125.3, 121.7, 39.7.

Preparation of (E)-4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 180)

Starting from ethyl 3-(3-bromophenyl)-3-oxopropanoate, a brown solid is obtained (7%).

¹H NMR (CDCl₃, 400 MHz): δ 8.30 (t, 1H, J=1.6 Hz), 8.00 (d, 1H, J=8 Hz), 7.77 (bs, 1H), 7.63 (dd, 1H, J=0.8 and 8 Hz), 7.52 (dd, 1H, J=2 and 7.6 Hz), 7.36 (t, 1H, J=8 Hz), 7.27 (m, 1H), 7.07 (dd, 1H, J=1.6 and 7.2 Hz), 3.55 (s, 2H).

¹³C NMR (CDCl₃, 100 MHz): δ 166.9, 157.3, 139.7, 139.3, 133.9, 130.7, 130.2, 128.8, 128.4, 126.9, 126.3, 125.3, 123.1, 121.7, 39.7.

Preparation of (E)-4-(3-(trifluoromethyl)phenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 181)

Starting from ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate, a brown solid is obtained (34%).

¹H NMR (CDCl₃, 400 MHz): δ 8.42 (s, 1H), 8.26 (d, 1H, J=7.6 Hz), 7.78 (bs, 1H), 7.76 (d, 1H, J=8.4 Hz), 7.63 (t, 1H, J=7.6 Hz), 7.54 (dd, 1H, J=2.4 and 8 Hz), 7.33-7.29 (m, 2H), 7.08 (dd, 1H, J=2.4 and 7.2 Hz), 3.60 (s, 2H).

Starting from 4-bromobenzene-1,2-diamine

A β-keto ester (0.5 mmol; 1 equiv.) is added to a stirred suspension of diamine (0.5 mmol; 94 mg; 1 equiv.) in toluene (2 ml).

The mixture is stirred at reflux (120° C.) for 3 h. The mixture is diluted with EtOAc, acidified (pH 5), extracted with EtOAc, filtered, evaporated and washed with Et₂O.

Preparation of (E)-7-bromo-4-m-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 182)

Starting from ethyl 3-oxo-3-m-tolylpropanoate, a brown solid is obtained (28%).

¹H NMR (CDCl₃, 400 MHz): δ 7.89 (m, 3H), 7.40-7.32 (m, 4H), 3.58 (s, 2H), 2.44 (s, 3H).

ESI+MS: calcd for C₁₆H₁₃BrN₂O: 328.02; found: 328.9 (MH⁺).

Preparation of (E)-7-bromo-4-(3-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 183)

Starting from ethyl 3-(3-methoxyphenyl)-3-oxopropanoate, a brown solid is obtained (10%). ESI+MS: calcd for C₁₆H₁₃BrN₂O₂: 344.02; found: 344.9 (MH⁺).

Preparation of (E)-7-bromo-4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 184)

Starting from 3-(3-nitrophenyl)-3-oxopropanoate, a brown solid is obtained (6.5%).

ESI+MS: calcd for C₁₅H₁₀BrN₃O₃: 358.99; found: 359.8 (MH⁺).

Preparation of (E)-7-bromo-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 185)

Starting from ethyl 3-(3-chlorophenyl)-3-oxopropanoate, a brown solid is obtained (23%).

ESI+MS: calcd for C₁₅H₁₀BrClN₂O: 347.97; found: 348.8 (MH⁺).

Preparation of (E)-7-bromo-4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 186)

Starting from ethyl 3-(3-bromophenyl)-3-oxopropanoate, a brown solid is obtained (10%).

ESI+MS: calcd for C₁₅H₁₀Br₂N₂O: 391.92; found: 392.8 (MH⁺).

Preparation of (E)-7-bromo-4-(3-(trifluoromethyl)phenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one (compound 186)

Starting from ethyl 3-(3-(trifluoromethyl)phenyl)-3-oxopropanoate, a brown solid is obtained (29%). ESI+MS: calcd for C₁₆H₁₀BrF₃N₂O: 381.99; found: 382.8 (MH⁺).

EXAMPLE 2 Demonstration of the Activity of the Compounds According to the Invention 1) Principle of the High-Throughput Screening:

A cell assay was developed in order to demonstrate the cytotoxic activity of ricin while at the same time being suitable for the constraints of high-throughput screening (see FIG. 1, diagrammatic representation of this assay). The use of such an assay has several advantages:

(i) selection of molecules which can act on the various stages of cell poisoning (receptor binding, internalization, intracellular trafficking, enzymatic activity, etc.); (ii) selection of molecules which penetrate the cell; (iii) elimination of cytotoxic compounds.

In addition, the assay used directly measures the ability of the cells to synthesize proteins, which makes it an excellent screening assay since this biosynthetic pathway is stopped by ricin.

The principle of the cell assay is the following: the compounds of combinatorial libraries are preincubated with ricin and the whole is added to the culture medium of human lung epithelial cells (A549 cells, 60 000 cells/well, [ricin]=10⁻¹⁰M) cultured on plates having a solid scintillant bottom (Scintiplates, GE). After incubation, the medium is removed and replaced with a leucine-free culture medium containing the radioactive tracer, which is [¹⁴C]-leucine (0.05 μCi/well). The incorporation of [¹⁴C]-leucine is then measured after a second incubation. The presence of the tracer in the cells reflects the presence of an inhibitor (C=50 μM) in the well (FIG. 1).

The yellow-colored wells are positive controls (A549 treated with ricin (10⁻¹⁰M) in the presence of 20 mM of lactose, which is an inhibitor of ricin binding to cells), whereas the green wells are negative controls (cells treated with ricin alone). The red wells are cells in contact with the compounds of the libraries in the presence of ricin (80 different compounds per plate, 50 μM final concentration).

The results of the screening carried out are represented in the graph of FIG. 2.

2) Implementation of the High-Throughput Screening: 2.1. Protective Activity Against Ricin Toxin of the Compounds According to the Invention

The compounds were tested on A549 cells at the concentration of 30 μM by incubation with various ricin concentrations (10⁻⁹ to 10⁻¹²M), with the protocol described previously for the high-throughput screening. The radioactivity measured is then proportional to the cell survival rate. Analysis of the data by nonlinear regression makes it possible to estimate the EC₅₀, i.e. the effective concentration for which 50% radioactive leucine assimilation is observed, which corresponds to 50% of viable cells. The higher the EC₅₀ value, the greater the cell protection, since a higher concentration of ricin is then necessary in order to generate the same cytotoxicity.

The results, presented in the table below, are indicated in the form of a protective index (PI=EC₅₀ compound/EC₅₀ ricin ratio): the higher it is, the greater the protection of the cells against the action of ricin (the effect is protective if the ratio is greater than 1).

No Structures Bio 19

1.31 3

2.65 7

1.07 9

1.88 148

2.82 21

1.01 122

1.49 128

1.30 64

1.16 65

1.61 94

1.18 89

1.41 1

1.58 123

1.02 113

1.09 121

1.225 110

3.13 32

1.16 109

1.32 78

1.09 79

1.02 80

1.05 81

1.03 75

1.62 15

4.64 111

3.07 5

2.13 124

1.08 26

1.06 27

1.23 86

2.24 77

1.15 84

1.25 83

1.05

1.07 120

1.09 28

2.52 24

1.49 56

1.09 36

2.28/ 3.57 50

1.22 53

1.17 102

1.34 99

1.09 105

1.38 106

3.64 108

1.20 107

2.33 54

1.17 55

1.21 59

1.30 132

1.03 133

1.10 51

1.063 165

1(a) 166

1.14 (a) 166

1.11 (a) 179

1.04 149

1.02 151

1.04 117

2.199 118

1.48 112

3.54 192

1.2 69

1.84 69

1.52 154

1.37 157

1.27 138

1.55 131

1.43 139

2.97 140

2.62 34

1.93 39

3.77 72

1.27 40

1.16 193

4.1 141

1.10 142

1.41 143

1.64 161

2.98

It is clearly observed that these compounds inhibit the cytotoxic action of ricin. Furthermore, they are the only inhibitors known at this time to protect A549 cells (human pulmonary epithelium) against ricin.

These compounds are the first inhibitors that are active on human pulmonary and digestive epithelial cells with respect to the toxic activity of ricin.

2.2. Protective Activity Against Diphtheria Toxin of the Compounds According to the Invention

The compounds were also tested on Vero cells (ATCC No. CCL-81) at the concentration of 30 μM by incubation with various concentrations of diphtheria toxin (10⁻⁹ to 10⁻¹²M) (Sigma), with the protocol described in point 2.1.

The results, presented in the table below, also represent a protective index (PI=EC₅₀ compound/EC₅₀ ricin ratio): the higher it is, the greater the protection of the cells against the action of diphtheria toxin.

Compound Structure Activity 5

2.2 9

1.7 39

1.5 110

2.6 111

1.8 112

3.6 139

1.7 140

3.0 

1. A method for the prevention and/or treatment of poisonings with at least one toxin with an intracellular mode of action or with at least one virus that uses the internalization pathway for infecting mammalian eukaryotic cells comprising administration to a subject in need thereof a compound of general formula (I):

in which: Cy represents a group chosen from:

W is chosen from a hydrogen atom or a halogen atom, Y is chosen from a hydrogen atom or a hydroxyl function and Z is a carbon atom or a bond (Cy is then a noradamantyl nucleus), wherein, when Cy is an adamantyl nucleus, the chain

is attached thereto in position 1 or 2, p represents 0 or 1; X represents either: a bond; an optionally unsaturated, optionally branched, C₁-C₆ alkyl chain which is optionally substituted with a phenyl radical, an acid function and/or a C₁-C₃ alkyl ester radical; said chain being optionally interrupted with an oxygen atom; —CO—, —O—CO—, —CO—NH— or

R¹ represents a radical containing 1 to 21 carbon atoms, which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom; said radical being optionally monosubstituted or disubstituted with a halogen atom, a —COOH, —OH or —NO₂ function, a C₁-C₃ alkyl radical, a C₁-C₃ alkoxy radical or a C₁-C₃ acyloxy radical; R² either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C₁-C₃ alkyl radical, a C₂-C₄ acyl radical or the radical

wherein, when R² is a bond, then the nitrogen atom bearing R² and X or the adjacent carbon atom (when p=1) are linked by a double bond, wherein X, R¹ and R² can form, with the adjacent nitrogen atom, an imidazole, oxazole, triazole or benzimidazole ring, which is optionally partially saturated, such as in particular dihydroimidazole, optionally substituted with a phenyl or pyridine radical; and the pharmaceutically acceptable salts thereof.
 2. The method as claimed in claim 1, characterized in that said compound of general formula (I) is such that R¹ is an optionally substituted phenyl radical and/or X is —CH₂— and/or R² is a hydrogen atom and/or W represents a Br atom.
 3. The method as claimed in claim 1, characterized in that said compound of general formula (I) is such that R¹ is the radical:

in which: R³ is chosen from a saturated or unsaturated cyclic radical containing 5 or 6 carbon atoms; a saturated or unsaturated bicyclic radical containing 9 or 10 carbon atoms; a saturated or unsaturated tricyclic radical containing 14 carbon atoms; a saturated or unsaturated heterocyclic radical containing 5 atoms; a saturated or unsaturated heterocyclic radical containing 6 atoms; a saturated or unsaturated biheterocyclic radical containing 9 or 10 atoms; said radicals being optionally substituted with at least one halogen atom, —NO₂, —OH or one C₁-C₃ alkyl radical; and R⁴ is chosen from —CO—O—, —N═CH— or —NH—CH₂—.
 4. The method as claimed in claim 3, characterized in that said compound of general formula (I) is defined by general formula (I′):

where X is either a bond or —CO—.
 5. The method as claimed in claim 1, characterized in that said compound of general formula (I) is chosen from: Compound 1: N-benzyladamantylamine Compound 2: N-(2-bromobenzyl)adamantylamine Compound 3: N-(3-bromobenzyl)adamantylamine Compound 4: N-(4-bromobenzyl)adamantylamine Compound 5: N-(3-fluorobenzyl)adamantylamine Compound 6: N-(3-hydroxybenzyl)adamantylamine Compound 7: N-(2-methoxybenzyl)adamantylamine Compound 8: N-(3-methoxybenzyl)adamantylamine Compound 9: N-(4-methoxybenzyl)adamantylamine Compound 10: N-(2-nitrobenzyl)adamantylamine Compound 11: N-(4-nitrobenzyl)adamantylamine Compound 12: N-(4-carbethoxybenzyl)adamantylamine Compound 13: 4-bromo-2-((1-adamantylino)methyl)phenol Compound 14: N-(2-bromo-5-nitrobenzyl)adamantylamine Compound 15: N-[(2-methoxy-5-bromo)benzyl]adamantylamine Compound 16: N-((pyridin-2-yl)methyl)adamantylamine Compound 17: N-((pyridin-3-yl)methyl)adamantylamine Compound 18: N-((pyridin-4-yl)methyl)adamantylamine Compound 19: N-((5-methylfuran-2-yl)methyl)adamantylamine Compound 20: N-((5-methylthiophen-2-yl)methyl)cyclohexanamine Compound 21: N-[(3-furyl)methyl]adamantylamine Compound 22: N-((1-methyl-1H-imidazol-5-yl)methyl)adamantylamine Compound 23: N-[(5-N-methylimidazolyl)methyl]adamantylamine Compound 24: Benzo[d][1,3]dioxol-4-yl)methyl)adamantylamine Compound 25: N-((5-nitrobenzo[d][1,3]dioxol-6-yl)methyl)adamantylamine Compound 26: N-((quinolin-3-yl)methyl)adamantylamine Compound 27: N-((quinolin-4-yl)methyl)adamantylamine Compound 28: N-((1-methyl-1H-indol-2-yl)methyl)adamantylamine Compound 29: N-phenethyladamantylamine Compound 30: N-(3-phenylpropyl)adamantylamine Compound 31: N-(2-(benzyloxy)ethyl)adamantylamine Compound 32: N-cinnamyladamantylamine Compound 33: N-methyl(3-bromobenzyl)adamantylamine Compound 34: N-benzyl-2-adamantylamine Compound 35: N-(2-bromobenzyl)-2-adamantylamine Compound 36: N-(3-bromobenzyl)-2-adamantylamine Compound 37: N-(4-bromobenzyl)adamantylamine Compound 38: N-(2-fluorobenzyl)-2-adamantylamine Compound 39: N-(3-fluorobenzyl)-2-adamantylamine Compound 40: N-(4-fluorobenzyl)-2-adamantylamine Compound 41: N-(3-hydroxybenzyl)-2-adamantylamine Compound 42: N-(2-methoxybenzyl)-2-adamantylamine Compound 43: N-(3-methoxybenzyl)-2-adamantylamine Compound 44: N-(4-methoxybenzyl)-2-adamantylamine Compound 45: N-(2-nitrobenzyl)-2-adamantylamine Compound 46: N-(4-nitrobenzyl)-2-adamantylamine Compound 47: N-(4-carbethoxybenzyl)-2-adamantylamine Compound 48: 4-bromo-2-((2-adamantylamino)methyl)phenol Compound 49: N-(2-bromo-5-nitrobenzyl)-2-adamantylamine Compound 50: N-(5-bromo-2-methoxybenzyl)-2-adamantylamine Compound 51: N-(5-fluoro-2-nitrobenzyl)-2-adamantylamine Compound 52: N-(2,5-difluorobenzyl)-2-adamantylamine Compound 53: N-((pyridin-2-yl)methyl)-2-adamantylamine Compound 54: N-((pyridin-3-yl)methyl)-2-adamantylamine Compound 55: N-((pyridin-4-yl)methyl)-2-adamantylamine Compound 56: N-((5-methylfuran-2-yl)methyl)-2-adamantylamine Compound 57: N-((5-methylthiophen-2-yl)methyl)-2-adamantylamine Compound 58: N-((furan-3-yl)methyl)-2-adamantylamine Compound 59: N-((1-methyl-1H-imidazol-5-yl)methyl)-2-adamantylamine Compound 60: N-[(5-N-methylimidazolyl)methyl]-2-adamantylamine Compound 61: Benzo[d][1,3]dioxol-4-yl)methyl)-2-adamantylamine Compound 62: N-((5-nitrobenzo[d][1,3]dioxol-6-yl)methyl)-2-adamantylamine Compound 63: N-((quinolin-3-yl)methyl)-2-adamantylamine Compound 64: N-((quinolin-4-yl)methyl)-2-adamantylamine Compound 65: N-((1-methyl-1H-indol-2-yl)methyl)-2-adamantylamine Compound 66: N-(1-(3-bromophenyl)ethyl)-2-adamantylamine Compound 67: N-benzhydryl-2-adamantylamine Compound 68: N-(2-(benzyloxy)ethyl)-2-adamantylamine Compound 69: N-(phenylpropyl)-2-adamantylamine Compound 70: N-(1-phenylethyl)-2-adamantylamine Compound 71: N-(1-(pyridin-2-yl)ethyl)-2-adamantylamine Compound 72: N-(2-adamantylmethyl)-1-(adamantyl)ethanamine Compound 73: N-methyl(3-bromobenzyl)-2-adamantylamine Compound 74: N-(3-bromobenzyl)-2-methylpropan-2-amine Compound 75: N-(3-bromobenzyl)-2,4,4-trimethylpentan-2-amine Compound 76: 2-(3-bromobenzylamino)-3-hydroxy-2-methylpropanoic acid Compound 77: 2-(3-bromobenzylamino)-2-(hydroxymethyl)propane-1,3-diol Compound 78: N-(3-bromobenzyl)cyclohexanamine Compound 79: 4-(3-bromobenzylamino)cyclohexanol Compound 80: N-(3-fluorobenzyl)cyclohexylamine Compound 81: 4-(3-fluorobenzylamino)cyclohexanol Compound 82: (1-(3-bromobenzylamino)cyclopentyl)methanol Compound 83: 1-(3-bromobenzylamino)cyclopentanecarboxylic acid Compound 84: N-(3-bromobenzyl)bicyclo[2.2.1]heptan-2-amine Compound 85: 2-(3-bromobenzylamino)bicyclo[2.2.1]heptane-2-carboxylic acid Compound 86: N-(3-bromobenzyl)noradamantylamine Compound 87: N-(3-bromobenzyl)-1-hydroxy-2-adamantylamine Compound 88: N-(3-bromobenzyl)-N-((benzo[d][1,3]dioxol-6-yl)methyl)(3-bromophenyl)methanamine Compound 89: 2-(3-bromobenzylamino)-2-(4-hydroxybenzyl)propanoic acid Compound 90: 2-(3,4-dihydroxybenzyl)-2-(3-bromobenzylamino)propanoic acid Compound 91: 2-(3-bromobenzylamino)-2-phenylbutanoic acid Compound 92: 2-(3-bromobenzylamino)-2,2-diphenylacetic acid Compound 93: methyl 2-(3-bromobenzylamino)-2-methyl-3-phenylpropanoate Compound 94: methyl 3-(3-bromobenzylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate Compound 95: N-(3-bromobenzyl)-9-methyl-9-azabicyclo[3.3.1]nonan-3-amine Compound 96: N-(3-bromobenzyl)benzo[d][1,3]dioxol-5-amine Compound 97: 2-(3-bromobenzylideneamino)-2-(3,4-dihydroxyphenyl)propanoic acid Compound 98: N-benzyl(3-bromophenyl)methanamine Compound 99: bis(3-bromobenzyl)amine Compound 100: N-(3-fluorobenzyl)(3-bromophenyl)methanamine Compound 101: N-(3-bromobenzyl)(1-methyl-1H-indol-2-yl)methanamine Compound 102: N-(3-bromobenzyl)-1-phenylethanamine Compound 103: N-(3-bromobenzyl)-1-(3-bromophenyl)ethanamine Compound 104: N-(3-bromobenzyl)-1-(pyridin-2-yl)ethanamine Compound 105: N-(3-bromobenzyl)quinuclidin-3-amine Compound 106: (1R*,5S*)—N-(3-bromobenzyl)bicyclo[3.3.1]nonan-9-amine Compound 107: N-(3-bromobenzyl)-8-methyl-8-aza-bicyclo[3.2.1]octan-3-amine Compound 108: N-(1-(3-bromophenyl)ethyl)adamantylamine Compound 109: N-(3-fluorobenzyl)noradamantylamine Compound 110: N-(3-bromobenzyl)adamantylamine hydrochloride salt Compound 111: N-(5-bromo-2-methoxybenzyl)adamantylamine hydrochloride salt Compound 112: N-(2-bromobenzyl)-2-adamantylamine hydrochloride salt Compound 113: (E)-N-(3-bromobenzylidene)adamantylamine Compound 114: (E)-N-(3-fluorobenzylidene)adamantylamine Compound 115: (E)-N-((1-methyl-1H-indol-2-yl)methylene)adamantylamine Compound 116: (E)-N-benzylideneadamantylamine Compound 117: (E)-N-(3-bromobenzylidene)adamantylamine Compound 118: (E)-N-(3-fluorobenzylidene)adamantylamine Compound 119: (E)-N-(3-bromobenzylidene)noradamantylamine Compound 120: (E)-N-((1-methyl-1H-indol-2-yl)methylene)noradamantylamine Compound 121: N-1-adamantylbenzamide Compound 122: N-2-adamantylbenzamide Compound 123: phenyl N-adamantylcarbamate Compound 124: N-adamantyl benzenesulfonamide Compound 125: N-adamantyl-N-(3-bromobenzyl)acetamide Compound 126: phenyl N-2-adamantylcarbamate Compound 127: N-adamantyl-N-(3-bromobenzyl)benzamide Compound 128: N-2-adamantyl benzenesulfonamide Compound 129: 1-(adamantyl)-3-phenylurea Compound 131: 1-(adamantyl)-1-(3-bromobenzyl)-3-phenylurea Compound 132: 1-(2-adamantyl)-3-phenylurea Compound 134: 1-(adamantyl)-2,5-dihydro-1H-imidazole Compound 135: 1-(adamantyl)-2,5-dihydrooxazole Compound 136: 1-(adamantyl)-1-phenyl-4,5-dihydro-1H-imidazole Compound 137: 1-(adamantyl)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazole Compound 136: N-(3-chlorobenzyl)adamantylamine Compound 139: N-(3-chlorobenzyl)-2-adamantylamine Compound 140: N-(3-iodobenzyl)-2-adamantylamine Compound 141: N-(2,2-diphenylethyl)-2-adamantylamine Compound 142: N-(naphthalen-1-ylmethyl)-2-adamantylamine Compound 143: N-(phenanthren-9-ylmethyl)-2-adamantylamine Compound 144: 4-((adamantylamino)methyl)benzoic acid Compound 145: adamantylamino-4-phenyl-1H-1,2,3-triazole Compound 146: adamantylamino-4-phenyl-1H-1,2,3-triazole Compound 147: 2-(adamantylamino-1H-1,2,3-triazol-4-yl)pyridine Compound 148: N-(2-bromo-5-nitrobenzyl)adamantylamine Compound 149: 2-(3-bromobenzylideneamino)-N-phenylbenzamide Compound 150: 2-(3-bromobenzylamino)-N-phenylbenzamide Compound 151: 2-(3-fluorobenzylideneamino)-N-phenylbenzamide Compound 152: (E)-2-((furan-2-yl)methyleneamino)-N-phenylbenzamide Compound 153: (E)-2-((furan-3-yl)methyleneamino)-N-phenylbenzamide Compound 154: (E)-2-((5-methylfuran-2-yl)methyleneamino)-N-phenylbenzamide Compound 155: (E)-2-(5-fluoro-2-nitrobenzylideneamino)-N-phenylbenzamide Compound 156: (E)-2-(4-fluorobenzylideneamino)-N-phenylbenzamide Compound 157 (E)-2-(2-fluorobenzylideneamino)-N-phenylbenzamide Compound 158: (E)-2-((1-methyl-1H-indol-2-yl)methyleneamino)-N-phenylbenzamide Compound 159: (E)-2-(5-bromo-2-hydroxybenzylideneamino)-N-phenylbenzamide Compound 160: 2-(2-fluorobenzylamino)-N-phenylbenzamide Compound 161: (E)-2-(2-(5-methylthiophen-2-yl)vinyl)-N-phenylbenzamide Compound 191: N-cinnamyl-2-adamantylamine Compound 192: N-(3-nitrobenzyl)-2-adamantylamine
 6. A compound of general formula (I):

in which: Cy represents a group chosen from:

W is chosen from a hydrogen atom or a halogen atom, Y is chosen from a hydrogen atom or a hydroxyl function and Z is a carbon atom or a bond (Cy is then a noradamantyl nucleus), wherein, when Cy is an adamantyl nucleus, the chain

is attached thereto in position 1 or 2, p represents 0 or 1; X represents either: a bond; an optionally unsaturated, optionally branched, C₁-C₆ alkyl chain which is optionally substituted with a phenyl radical, an acid function and/or a C₁-C₃ alkyl ester radical; said chain being optionally interrupted with an oxygen atom: —CO—, —O—CO—, —CO—NH— or

R¹ represents a radical containing 1 to 21 carbon atoms, which is optionally branched and/or cyclic, and saturated or unsaturated, in which one or more of the carbon atoms can be replaced with a nitrogen, oxygen and/or sulfur atom; said radical being optionally monosubstituted or disubstituted with a halogen atom, a —COOH, —OH or —NO₂ function, a C₁-C₃ alkyl radical, a C₁-C₃ alkoxy radical or a C₁-C₃ acyloxy radical; R² either represents a bond or is chosen from a hydrogen atom, an optionally unsaturated, optionally branched, C₁-C₃ alkyl radical, a C₂-C₄ acyl radical or the radical

wherein, when R² is a bond, then the nitrogen atom bearing R² and X or the adjacent carbon atom (when p=1) are linked by a double bond, wherein X, R¹ and R² can form, with the adjacent nitrogen atom, an imidazole, oxazole, triazole or benzimidazole ring, which is optionally partially saturated, such as in particular dihydroimidazole, optionally substitute with a phenyl or pyridine radical; and the pharmaceutically acceptable salts thereof, except for compounds 1, 6, 8, 11, 18, 29, 30, 34, 74, 78, 98, 100, 113, 114, 116, 121, 122, 124, 128, 135, 145 and 161 in Table 1 of the specification.
 7. A method for the prevention and/or treatment of poisonings with at least one toxin with an intracellular mode of action or with at least one virus that uses the internalization pathway for infecting mammalian eukaryotic cells comprising administration to a subject in need thereof a compound which is a benzodiazepine derivative of general formula (II):

where A and B represent a carbon atom or a nitrogen atom with the proviso that, if A=N then B=C, and if A=C then B=N; R³ is chosen from a hydrogen or halogen atom; a C₁-C₆ alkyl radical, a C₁-C₆ alkoxy radical or a C₁-C₆ acyloxy radical, these radicals being optionally substituted with a C₁-C₆ alkoxy radical; an aryloxy radical or a heteroaryloxy radical; R⁴ either represents a bond or is chosen from a hydrogen atom, a C₁-C₃ acyloxy radical, a C₁-C₃ alkoxy radical or a phenyl; R⁵ either represents a bond or is chosen from a hydrogen atom; a C₁-C₃ alkyl radical; a C₁-C₃ alkoxy radical; a C₁-C₃ acyloxy radical or a phenyl radical which is optionally substituted with an —OH function and/or a halogen atom, a C₁-C₃ alkyl radical, a C₁-C₃ alkoxy radical, a C₁-C₃ acyloxy radical, an —NO₂ or —CF₃ function, or a radical

wherein R₄ and R₅ cannot simultaneously represent a bond and that, when one of the two is a bond, then A and B are linked by a double bond; and that, when B is a carbon atom, R⁵ can also form, with the hydrogen atom borne by the carbon adjacent to B, a ring of 5 or 6 atoms, optionally substituted with a phenyl radical, optionally interrupted with a nitrogen, sulfur or oxygen atom; and also the pharmaceutically acceptable salts thereof.
 8. The method as claimed in claim 7, characterized in that said compound of general formula (II) is such that R³ is a bond and/or R⁴ represents a hydrogen atom and/or R⁵ represents a phenyl radical and/or, when A is a carbon atom, then R⁴ is a phenyl radical, and/or, when B is a carbon atom, then R⁵ is a phenyl radical.
 9. The method as claimed in claim 7, characterized in that said compound of general formula (II) is chosen from: Compound 162: 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one Compound 163: 7-bromo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one Compound 164: 7-bromo-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one Compound 165: 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one Compound 166: 4-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one Compound 167: 4,5-dihydro-7-methoxy-5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one Compound 168: Ethyl 4-oxo-2-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carboxylate Compound 169: 5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one Compound 170: 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one Compound 171: 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one Compound 172: 4-(2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 173: 4-(5-bromo-2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 174: 4-(5-fluoro-2-hydroxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 175: 8-bromo-3-phenyl-3,3a,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepin-4(2H)-one Compound 176: 4-m-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 177: 4-(3-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 178: 4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 179: 4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 180: 4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 181: 4-(3-(trifluoromethyl)phenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 182: 7-bromo-4-m-tolyl-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 183: 7-bromo-4-(3-methoxyphenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 184: 7-bromo-4-(3-nitrophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 185: 7-bromo-4-(3-chlorophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 186: 7-bromo-4-(3-bromophenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 187: 7-bromo-4-(3-(trifluoromethyl)phenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one Compound 193: 7-bromo-5-phenyl-4-propionyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one
 10. A compound which is a benzodiazepine derivative of general formula (II):

where A and B represent a carbon atom or a nitrogen atom with the proviso that, if A=N then B=C, and if A=C then B=N; R³ is chosen from a hydrogen or halogen atom; a C₁-C₆ alkyl radical, a C₁-C₆ alkoxy radical or a C₁-C₆ acyloxy radical, these radicals being optionally substituted with a C₁-C₆ alkoxy radical; an aryloxy radical or a heteroaryloxy radical; R⁴ either represents a bond or is chosen from a hydrogen atom, a C₁-C₃ acyloxy radical, a C₁-C₃ alkoxy radical or a phenyl; R⁵ either represents a bond or is chosen from a hydrogen atom; a C₁-C₃ alkyl radical; a C₁-C₃ alkoxy radical; a C₁-C₃ acyloxy radical or a phenyl radical which is optionally substituted with an —OH function and/or a halogen atom, a C₁-C₃ alkyl radical, a C₁-C₃ alkoxy radical, a C₁-C₃ acyloxy radical, an —NO₂ or —CF₃ function, or a radical

wherein R₄ and R₅ cannot simultaneously represent a bond and that, when one of the two is a bond, then A and B are linked by a double bond; and that, when B is a carbon atom, R⁵ can also form, with the hydrogen atom borne by the carbon adjacent to B, a ring of 5 or 6 atoms, optionally substituted with a phenyl radical, optionally interrupted with a nitrogen, sulfur or oxygen atom; and also the pharmaceutically acceptable salts thereof, except for compounds 162, 163, 164, 165, 166, 167, 169, 170, 171 and 193 in Table 2 of the specification.
 11. A pharmaceutical composition comprising the compound as claimed in claim 6 or
 10. 12. The pharmaceutical composition as claimed in claim 11, further comprising at least one pharmaceutically acceptable vehicle.
 13. The pharmaceutical composition as claimed in claim 11, characterized in that said composition is intended to be administered orally, aerially, parenterally or locally.
 14. The method as claimed in any one of claims 1 or 7 wherein the poisoning is ricin poisoning.
 15. The method as claimed in claim 14, characterized in that said compound is chosen from compounds 1, 3, 5, 9, 15, 19, 24, 28, 34, 36, 39, 59, 65, 67, 68, 69, 75, 86, 89, 105, 106, 109, 110, 111, 112, 117, 118, 122, 128, 131, 138, 139, 140, 142, 143, 148, 154, 161 and 193 in Tables 1 and 2 of the specification.
 16. The method as claimed in claim 14, characterized in that the compound of general formula (I) is defined by general formula (I.1):

in which: Cy represents a group chosen from:

Z is a carbon atom or a bond (Cy is then a noradamantyl nucleus), wherein when Cy is an adamantyl nucleus, the nitrogen atom is attached thereto in position 1 or 2, R¹ represents: a phenyl ring, optionally substituted with an —OCH₃ radical in the para-position with respect to the carbon atom bonded to the —CH₂—NH-Cy chain; said ring being alternatively optionally substituted with a halogen atom in the meta-position with respect to the carbon atom bonded to the —CH₂—NH-Cy chain, and in this case, said ring optionally bears a second substitution in the para-position with respect to said halogen atom, said second substitution being chosen from —NO₂ and —OCH₃; an indole, imidazole or furan ring substituted with a methyl radical; a benzo(1,3)dioxolo ring, a naphthalenyl ring or a phenanthrenyl ring; and the pharmaceutically acceptable salts thereof.
 17. The method as claimed in claim 16, characterized in that said compound of general formula (I.1) is chosen from compounds 1, 3, 5, 9, 15, 19, 24, 28, 34, 36, 39, 59, 65, 86, 109, 110, 111, 112, 138, 139, 140, 142, 143 and 148 in Table 1 of the specification.
 18. The method as claimed in claim 14, characterized in that the compound of general formula (I) is defined by general formula (I.2):

in which X represents —(CH₂)₂—O—CH₂—, —(CH₂)₃—, —CO— or —SO₂—, and the pharmaceutically acceptable salts thereof.
 19. The method as claimed in claim 18, characterized in that said compound of general formula (I.2) is chosen from compounds 68, 69, 122 and 128 in Table 1 of the specification.
 20. The method as claimed in claim 14, characterized in that the compound of general formula (I) is defined by general formula (I.3):

in which W represents a halogen atom, and the pharmaceutically acceptable salts thereof.
 21. The method as claimed in claim 20, characterized in that said compound of general formula (I.3) is chosen from compounds 117 and 118 in Table 1 of the specification.
 22. The method as claimed in claim 14, characterized in that the compound of general formula (I) is defined by general formula (I.4):

in which Y is O or S, and the pharmaceutically acceptable salts thereof.
 23. The method as claimed in claim 22, characterized in that said compound of general formula (I.3) is chosen from compounds 154 and 161 in Table 1 of the specification.
 24. The method as claimed in any one of claims 1 or 7 wherein the poisoning is from diphtheria toxin.
 25. The method as claimed in claim 24, characterized in that the compound of general formula (I) is defined by general formula (I.5):

in which: Cy represents a group:

to which the nitrogen atom is attached in position 1 or 2, W and W′ are, independently of one another, chosen from a hydrogen atom, a halogen atom and a C₁-C₃ alkoxy radical, and the pharmaceutically acceptable salts thereof.
 26. The method as claimed in claim 25, characterized in that said compound of general formula (I) is chosen from compounds 5, 9, 39, 110, 111, 112, 139 and 140 in Table 1 of the specification.
 27. A compound of general formula (I.1)

and the pharmaceutically acceptable salts thereof, in which: Cy represents a group chosen from:

Z is a carbon atom or a bond (Cy is then a noradamantyl nucleus), wherein when Cy is an adamantyl nucleus, the nitrogen atom is attached thereto in position 1 or 2, R¹ represents: a phenyl ring, optionally substituted with an —OCH₃ radical in the para-position with respect to the carbon atom bonded to the —CH₂—NH-Cy chain; said ring being alternatively optionally substituted with a halogen atom in the meta-position with respect to the carbon atom bonded to the —CH₂—NH-Cy chain, and in this case, said ring optionally bears a second substitution in the para-position with respect to said halogen atom, said second substitution being chosen from —NO₂ and —OCH₃; an indole, imidazole or furan ring substituted with a methyl radical; a benzo(1,3)dioxolo ring, a naphthalenyl ring or a phenanthrenyl ring. 